Institute of Genetics & Molecular & Cellular Biology

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Institute of Genetics & Molecular & Cellular Biology contents

Foreword 2

Academics 4

Development & Stem Cells 6

Cancer & Functional Genomics 34

Integrated Structural Biology 62

Translational Medicine & Neurogenetics 80

ICS 100

Platforms 102

Core facilities 108

Facts & Figures 110

Staff scientists 112

Prizes & Distinctions 116

Publications until June 2010 117

Publications 2009 120

Where we are 126 Olivier Pourquié, IGBMC Director

The IGBMC is one of the leading centers in bio- that are directly interested in biological questions logical research in Europe. It was founded in 1994 with immediate clinical relevance, such as human by Pierre Chambon, one of the world’s leading genetic diseases. figures in biomedical sciences. With its 768 staff One of IGBMC’s major assets are its excellent the Institute represents one of the largest French core facilities and its outstanding technological biomedical research units associating INSERM, platforms, which provide accessible state of the CNRS and the University of Strasbourg. The art technologies to the institute’s scientists. One IGBMC is located close to Strasbourg, a cosmo- of these platforms, the Mouse Clinical Institute politan city hosting the European parliament on (ICS), is rather unusual in that it is a large struc- the frontier between France and Germany. ture employing more than 100 The IGBMC is a highly international center with people exclusively dedicated to 43 Groups 48 different nationalities represented among its mouse technology. Its activities 106 Staff scientists personnel and all activities in the Institute are car- range from transgenic mouse ried out in English. models production to complex 121 Postdoctoral fellows

The 43 independent research teams work on a phenotyping strategies inclu- 118 PhD students broad array of topics, ranging from the analysis of ding behavioral and metabolic 37 Master students protein structure to human genetics. The research analyses. In the following pages themes are organised into the following four you will find an overview of 293 Engineers & Technicians transversal Programmes. The Integrated Structural IGBMC’s broad range of re- Biology Programme consists of teams studying the search activities and technology 93 Administrators & General services structure of proteins using a variety of approaches support, highlighting our sti- ranging from diffraction analysis and computer mulating environment which modeling to state of the art electron microscopy. aims to foster excellent training The Programme Functional Genomics and Cancer and cross-discipline collabora- is centered on the analysis of the regulation of gene tions. < expression and epigenetics. Several groups in this Programme are also interested in the deregulation of these mechanisms that often lead to cancer. The Foreword Programme Development and Stem Cells brings to- With the ambition of creating a European centre of excellence in medical research, the IGBMC was founded by gether research groups interested in the formation Pierre Chambon and installed on its present site in 1994 of the embryo and in stem cell biology in a variety with the assistance of INSERM, CNRS, the University of model systems. Within this Programme, we of Strasbourg and the American laboratories of Bristol also see an interface emerging with the physical Myers-Squibb (BMS). Between 2002 and 2009, following on from Pierre Chambon, the Direction of the IGBMC sciences, associating physicists and cell biologists was assured by Dino Moras and Jean-Louis Mandel, two in the study of complex processes such as mor- scientists of international reputation. phogenesis. The Programme Translational Medi- In October 2009, Olivier Pourquié, a pioneer in research cine and Neurogenetics links all the research teams on muscles and skeletal development, elected to return to France to lead the IGBMC, following several years spent in the United States at the Howard Hughes Medical Ins- titute. His principal objective is to confirm and strengthen the status of the IGBMC on the national and international scientific stage. 3 academics academics

● Students & Post-docs Board • Seminars: We organize career development seminars for our community. With its recently launched International PhD Since October 2004, the Students and Post-Docs • Guides: Three guides have been developed to Programme, the IGBMC successfully attracts and Board (SPB) of the IGBMC has been working actively facilitate a newcomers’ life: a welcome guide, living recruits outstanding students from around the to promote and enhance the scientific and social ex- in Strasbourg, information guide about the University world via a call for applications. In this framework, change between the students and post-docs of the Ins- and the Graduate School and fellowships. we provide dedicated scientific and socio-professio- titute, the scientific programmes, the core facilities as International Cine-Club: nal training to our students, in accordance with the well as the platforms. It also links IGBMC’s students/ • Launched in December Graduate School. The training benefits notably from post-docs with the Direction, and the Life Sciences 2007, the Cine-Club invites staff to discover and the excellent scientific environment and is tailored to Graduate School of the University of Strasbourg. After learn from cultures that are represented at IGBMC. the needs of the students. The courses typically co- six years of continual growth and improvement, the Movies are selected and introduced by a student/post- ver all areas of modern biology and state-of-the art SPB has become an important partner working in a doc from abroad that is willing to share some cultural technologies offered at the Institute. The training of close relationship with the IGBMC administration. aspects about his or her country. our students is further enriched by a great diversity of • French and English lunches: Once a month, the SPB additional activities, of which a flavor is given here: arranges a lunch to allow participants to practice their • Special Seminar Series: Eminent international language skills: speaking either French with native scientists are invited to give a lecture as part of the French speakers or English with English natives. IGBMC Special Seminar Series. • Social events: The SPB often organizes parties and • Lunches with prominent scientists: Students have ● Training at IGBMC sport events to bring together students and post-docs the opportunity to lunch with the Special Seminar to strengthen bonds and to promote interactions in a speakers in an informal setting. As one of the leading European centers for biomedi- different setting. • Student Special Lecture: Students have the cal research, the IGBMC provides an outstanding re- • Retreats: In June 2010, the SPB organized the first opportunity to invite an outstanding scientist to give search and training environment. With 239 students retreat for students and post-docs in a relaxed setting the Student Special Lecture. and post-docs from over 40 countries, we offer a very in the Vosges Mountains.< lively and dynamic setting, fostering interactions at • Internal seminars and retreats: Internal seminars give the IGBMC and beyond. students and post-docs the opportunity to present all The SPB organizes the following activities: of their work to IGBMC. Retreats organized by the The IGBMC accepts about 37 Master Students and scientific Programme offer a more informal setting to • Poster sessions: On a monthly basis, students and The International PhD Programme 25 PhD students annually, who are exposed to the present findings and to discuss and share knowledge post-docs present their research projects. Staff from Programme Coordination: Dr. Astrid Lunkes with more senior scientists. PhD Programme Committee: latest technological developments and are trained un- core facilities and platforms are also invited to present Dr. Elisabeth Georges-Labouesse, Dr. Sophie Jarriault, der the supervision of IGBMC group leaders across • Award: Each year, a student is awarded a travel their activities. Dr. Hélène Puccio, Dr. Evi Soutoglou, Dr. Laszlo Tora, Dr. Bernardo Reina-San-Martin, Dr. Marat Yusupov the Institute’s broad range of research fields. The stu- fellowship to attend a scientific meeting. • Scientific workshops: Three workshops are organized dents are generally enrolled at the Life Sciences Gra- Student affairs: Dr. Katia Befort • International meetings: Scientific meetings are every year with the assistance of platforms and The PhD Programme Administrator: Laetitia Gonzalez duate School of the University of Strasbourg, which organized on a regular basis and provide our younger researchers of the Institute. Topics includes: Microarray oversees the thesis progress and delivers the PhD cer- Students & Post-doc Board researchers with the opportunity to meet outstanding Analysis; Bioinformatics in the post-genomics area; Coordination & communication: Irène Yujnovsky tificate. Several IGBMC researchers teach at the Uni- speakers from different fields. 3D Structure Visualization and Functional Genomics. Workshop: Fabrice Klein versity, including the medical school, thereby promo- Two of these workshops have been part of the training Alumni & guides: Pierre Antony, Johann Boehm ting links between the University and IGBMC. Information package: Angelita Simonetti, within the IGBMC International PhD Programme Thomas Hussenet since 2009. Web site: Florent Colin, Pierre-Eric Lutz Poster sessions: Thomas Daniel, Jérôme Mastio, Adrien Rousseau Events: Sara Milosevic, Elisabeth Daguenet, Martin Moune-Dimala

5 Unravelling the mystery of cell differentiation

"Understanding how cells differentiate and how they organize in a 3-dimensional space should enable us to find tools to regenerate human tissues, or to reduce the risk of cancer". M. Labouesse

The Development and Stem Cells Pro- that characterize the toti/pluripotence of gramme features 12 teams using the fruit fly, stem cells. Some specific questions are zebrafish, worm, chicken and the mouse as “How do early mouse blastomeres remain models of interest. The unifying theme of totipotent?”, “how are pancreas endocrine the Programme is cell plasticity, either at the cells made different from each other?” “How nuclear level as it pertains to the mechanisms does a pluripotent progenitor restrict its that control stem cell maintenance and cell potential to generate only glial or neuronal fate reprogramming, or at the cellular level, progenitors?” “How do germ cells differen- with regard to the mechanisms that control tiate into male and female cell shape changes during morphogenesis. gametes?” “How do muscle 13 Groups While we all focus on fundamental issues, precursors arise from the most of us develop models of human di- presomitic mesoderm?”, 23 Staff scientists seases such as, cardiovascular diseases, retinal “how does a cell reprogram 31 Postdoctoral fellows degeneration, scoliosis, Crohn’s disease, dia- its identity?” The different 23 PhD students betes, infertility and cancer, among others. labs approach these questions through a combination 33 Engineers/Technicians Stem cells and reprogramming of genetic and cell biology Currently two- thirds of the teams aim to de- analyses in mouse, chicken, 1 Assistant fine the genetic and epigenetic Programmes zebrafish, fly, worm, as well as high throughput proteomic and sequencing methods.

Mouse and chicken Morphogenesis •Pancreas development and diabetes Other teams aim to understand how cells •Integrin signaling in organ morphogenesis •Retinoic acid signaling and neuronal cell fate communicate during late stages of em- •Role of retinoic acid signaling in germ cell specification • Progenitor germ cells and iPS bryogenesis when organs achieve their final •Somitogenesis and PSM extension functional shape. Imaging and cell biology Development •Epigenetic marks in maintenance of blastomere identity are central to the approaches developed and Zebrafish •Somitogenesis more recently, the input of physics has be- & Stem cells •Blood flow and cardiovascular development come key to these developments. Some spe- •Cilia in development cific questions being asked are “How do cells Fruit fly •Role of miRNAs in neural differentiation collectively migrate to their final positions?” •Collective cell migration •Choice between glial and neuronal differentiation “How do cells interact with the extracellular Worm matrix to define organ shape?” “How does •Cell fate reprogramming a cell change its shape?” and “What is the •Impact of cell division on cellular potential n •Secretion and lumen formation impact of forces on organ formation?” •Forces in embryonic morphogenesis Physics and biology •In vitro modeling of cell shape change •Cytokinesis in fission yeast

7 Roles of retinoic acid

in mouse development and physiology Further work will aim at elucidating common molecular mechanisms operating during neurogenesis within the developing telencephalon and the sensory neurons. This work will also contribute to an understanding of molecular pathways under retinoic acid control that are involved in highlights neural progenitor renewal, fate and differentiation. The pathophysiological consequences of manipulating retinoic acid production or RAR/RXR signaling in specific cell • Central Nervous System Patterning: We populations will also be investigated. < revealed that retinoic acid acts antagonistically to FGFs, but is required to potentiate Sonic hedgehog signaling, during elongation of embryonic trunk structures and patterning of the neural future the shaping

tube.

●Sensory Organ Development: Several molecular and cellular alterations resulting from invalida- Pascal Dollé ted retinoic acid signaling within the embryonic retina, the inner ear, and the olfactory placode 1 were characterized in our laboratory. Studying developmental genes: When «collinearity» ●Brain Development and Physiology: We unravel- leads to complexity led specific roles of retinoid signaling in higher Pascal Dollé received his medical degree probing complexity brain functions including motor control, co- Development of the vertebrate nervous system results gnitive functions and emotional processing. We in 1992 at Louis Pasteur University in Strasbourg, France. Following a research from an interplay between all major embryonic signaling found that RARbeta signaling controls the deve- internship on developmental biology and pathways and requires coordination of many embryonic lopment of a subpopulation of dopaminoceptive embryology with Denis Duboule and Pierre events including axial patterning, lateral inhibition, proge- neurons in the striatum involved in motor control, and Chambon, he obtained a PhD in1992 on nitor fate determination, axonal guidance, and ectomesen- that RXRgamma inactivation results in depressive beha- the developmental expression features chymal transformation giving rise to neural crest. Sensory vior due to impaired dopamine D2 receptor function in the nucleus accumbens. of murine Hox genes and was one of the systems are formed by direct out-growth and evagination pioneers of the study of knock-out mice in of brain neuroepithelium in the case of the retina, and the ●Mouse Models: Novel conditional alleles were generated this gene family. In parallel, Pascal worked inductive processes leading to the formation of ectoder- to study the function of the main retinol dehydrogenase on the characterization of retinoic acid mal placodes generating the lens, the embryonic inner ear acting during development, and to assess the roles of re- receptors function during development. In (otocyst), and the prospective olfactory epithelium. tinoids produced by specific neuronal populations and by 1992, he joined Pierre Chambon’s team and Our team is interested in deciphering some of the highly Krzyzosiak A, Szyszka-Niagolov M, Wietrzych M, Go- n baille S, Muramatsu S, Krezel W. Retinoid X Receptor the meninges. characterized several functions of RALDH2, pleiotropic functions of the vitamin A derivative retinoic Gamma Control of Motivated Behaviours involves a key enzyme involved in retinoic acid Dopaminergic Signalling in Mice. acid, and its nuclear receptors (RARs/RXRs), in these Neuron. 66:908-920. (2010). synthesis during embryogenesis. In 2001, he processes. We are using the mouse and chicken systems created his own team whose current focus is Lin SC, Dollé P, Ryckebüsch L, Noseda M, Zaffran S, 1- Analysis of neuronal progenitor to invalidate specific actors of this signaling pathway using Schneider MD, Niederreither K. Endogenous retinoic subpopulations in the developing on the development of the nervous system targeted gene inactivation, as well as pharmacological and acid regulates cardiac progenitor differentiation. cerebral cortex. and sensory organs. n Proc Natl Acad Sci U S A. 107(20):9234-9. (2010). 2- Distribution of stem cells (green) siRNA approaches. This work permits us to show that the among differentiating heart myocardial fine tuning of the activity of two classes of enzymes ca- Ribes V, Le Roux I, Rhinn M, Schuhbaur B, Dollé P. Early mouse caudal development relies on cross- cells (red). talyzing the synthesis (retinaldehyde dehydrogenases), or talk between retinoic acid, Shh and Fgf signalling the catabolism (CYP26 cytochromes), of retinoic acid in pathways. Development. 136(4):665-76. (2009). specific cell populations, is critical for the development of Niederreither K, Dollé P. Retinoic acid in develop- < ment: towards an integrated view. the central nervous and sensory systems. Nat Rev Genet. 9(7):541-53. (2008). 2 9 Integrin function and signaling in tissue

morphogenesis, integrity and homeostasis Currently we concentrate our efforts on the role of integrins in the epithelial tissues of skin and intestine. Of interest is the fact that in adults these two tissues also undergo tissue renewal and are submitted to mechanical forces. Both epithelia possess hemidesmosomes. These anchoring highlights junctions at the basal pole of cells are molecular complexes which play a crucial role in the control of epithelial cell shape and polarity. In particular, they ensure the link with • We have found that α6β4 integrin in the he- the basement membrane outside the cell and the keratin midesmosome is essential for epidermal/dermal cytoskeletal network inside the cells. These junctions attachment. This integrin and laminin ligands are also important in tissue integrity during stress. Using are implicated in genetic forms of epidermolysis

shaping the future the shaping mouse genetics and cellular approaches, we hope to gain

bullosa in human patients. insight about the signaling pathways that are implicated in the formation and function of these junctions.< • By studying double-mutant mice for integrins to overcome functional redundancy, we have been able to reveal novel roles for this fa- Elisabeth Georges-Labouesse mily in tissue morphogenesis processes such as formation of the apical ectodermal ridge in the limb and neural tube closure. Cellular and development 1 biology in vivo • Our team was the first to elucidate the role of After earning a master’s degree in Virology, an integrin in brain and retinal layer organization. probing complexity Elisabeth Georges-Labouesse obtained her Tissue morphogenesis and function involve changes in cell PhD at the Pasteur Institute UPMC (Paris) shape, cell adhesion and migration. These events which on cutaneous papillomavirus and analyzed implicate cell-cell or cell-extracellular matrix (ECM) inte- the viral Programme, which depended on epidermal cell differentiation steps. She ractions are tightly regulated. • We have found that the Nck interacting kinase (NIK) became a CNRS research associate in 1985 We are interested by cell-ECM interactions mediated by is a molecular partner for integrin β1. Our recent studies and was appointed a post-doctoral position the integrin family of adhesion receptors. By binding spe- suggest that it is the α5β1 integrin heterodimer, a fibro- in 1989 at MIT, Cambridge, US with Richard cific ECM ligands through their extracellular domains and nectin receptor, which interacts with NIK, notably during n Hynes. While conducting her research at MIT, recruiting signaling molecules and cytoskeletal elements in neuronal migration. she focused on the role of extracellular ma- the cytoplasm, integrins serve as sensors of the milieu for Marchetti G, Escuin S, van der Flier A, De Arcangelis trix proteins in tissue architecture by using the cells and participate in the building of the appropriate A, Hynes RO, Georges-Labouesse E. Integrin alpha- mutant mice. Her findings showed that fi- cellular responses. 5beta1 is necessary for regulation of radial migration of cortical neurons during mouse brain development bronectin was involved in somite organiza- Perturbations of integrins/ECM lead to severe pathologi- Eur J Neurosci. 31:399-409. (2010). tion. In 1996 she discovered the essential cal conditions (developmental defects, congenital muscu- Wu C, Ivars F, Anderson P, Hallmann R, Vestweber D, role of a6 integrin in hemidesmosomes for lar dystrophies, skin blistering and cancer). Our goal is to Nilsson P, Robenek H, Tryggvason K, Song J, Korpos E, Loser K, Beissert S, Georges-Labouesse E, So- dermal-epidermal attachment. In 2010 Elisa- understand the cellular and molecular mechanisms of in- rokin LM. Endothelial basement membrane laminin 1- beth’s work continues to focus on the role of alpha5 selectively inhibits T lymphocyte extravasation Localisation of integrin α6 at the tegrin activity in vivo and address questions such as tissue into the brain. Nat Med. 15(5):519-27. (2009). basal pole of the basal keratinocytes integrins in development and the compre- and stage requirements of integrins, ligand specificity in and hair follicle in skin. A mouse skin hension of the integrin signaling pathway Rodius S, Indra G, Thibault C, Pfister V, Georges-La- section was stained with an antibody vivo, signaling pathways, relevance to human pathologies. bouesse E. Loss of alpha6 integrins in keratinocytes in vivo, using in-utero electroporation, while against α6 integrin (green). DAPI < leads to an increase in TGFbeta and AP1 signaling equally studying the mechanisms of epithe- To this end, we have mostly used mouse genetics. and in expression of differentiation genes. staining (blue) labels nuclei. J Cell Physiol 212(2):439-49. (2007). 2- Plectin (red) and actin cytoskeleton lium organization and maintenance of their (green) of a migrating Caco2 cell. n Haubst N, Georges-Labouesse E, De Arcangelis A, integrity in skin and intestine. Mayer U, Gotz M. Basement membrane attachment is dispensable for radial glial cell fate and for proliferation, but affects positioning of neuronal subtypes. Development 133(16):3245-54. (2006). 2 11 Cellular and molecular mechanisms

of nervous system differentiation The integration of complex molecular cascades and cell interactions secures the differentiation of the diverse cell types and tissues that compose a multicellular organism. Modern biology tackles the molecular, epigenetic and cellular mechanisms underlying these events with highlights unprecedented resolution in space and time. We are convinced that understanding how cells enter a specific differentiative pathway and attain their appropriate • Cell differentiation and plasticity: We identi- position requires a multidisciplinary approach that straddles fied the glial lineages and the glial determinant, genetics, molecular and cellular biology, imaging and Glide/Gcm transcription factor, necessary to induce gliogenesis and sufficient to reprogram informatics.

cells towards the glial fate. We determined Gcm future the shaping Our in vivo and in vitro studies will also address the molecular cascade and provided evidence for conservation of these pathways throughout evolution. < evolutionary conservation.

• Collective cell migration: We identified a glial migratory chain in the fly nervous system and Angela Giangrande specific cell interactions required for collective Drosophila’s brain migration by genetic, ablation and time-lapse 1 approaches. Glia interacts with the neuronal After studying thalassemia at Bari Univer- substrate to gain directionality. Also, glial cells at sity in Italy, Angela Giangrande joined G. probing complexity the chain tip (pioneers) explore the environment Richards’ team in 1984 and obtained her and trigger the movement of following glia. In PhD in 1988 on transcription regulation in A major challenge in developmental biology is to unders- addition, homotypic interactions within the mi- Drosophila. During her postdoc research tand how cell diversity is generated and how cells inte- gratory unit control the extent of migration and with J. Palka at the University of Washington ract to build the sophisticated metazoan architecture. In chain integrity. (Seattle) she began a long fascination with humans, defects in such events lead to severe pathologies, the development of the Drosophila nervous from mental retardation to cancer. • An animal model for human pathologies: We characte- system where she discovered the origin of Evolutionary conservation, sophisticated genetics and rized a molecular pathway linked to the Fragile X Mental adult peripheral glial cells. simple organization make the fly an ideal tool to study Retardation Protein, the mutation of which induces most Since 1992, she has led a team on nervous these events in vivo and in vitro, at cellular resolution. The frequent cognitive defects in humans. We also created a system differentiation and has studied mo- nervous system constitutes one of the most complex tis- transgenic model for a severe and frequent form of human lecular and cellular associated mechanisms. retinal degeneration (Retinitis Pigmentosa). n sues, made of neurons and glia of different types. These She uses the Drosophila as a model to study cells arise from multipotent precursors or stem cells. The conserved mechanisms and molecules. On analysis of the signals controlling stem cell differentiation Su-chun Ho M, Chen H, Chen M, Jacques C, Gian- glial differentiation, her work led to the identi- grande A, and Chien C-T. Gcm protein degradation and reprogramming has recently drawn much attention, mediated by F-box E3 ligases suppresses prolifera- fication and characterization of the glial deter- due to potential medical applications. tion of glial progenitors. minant Glide/Gcm (1996). She now focuses PNAS. 106:6778-83. (2009). on the mechanisms controlling cell plasticity Our goal is to study the molecular and the epigenetic 1- Pupal eye triple Aigouy B, Lepelletier L, and Giangrande A. Chain and collective cell migration. Her research on events controlling cell differentiation and reprogramming. migration requires pioneer cells. labeled with glia (red), During development, many cells move as cohorts to attain J Neurosci. 28:11635-41. (2008). photoreceptor (green) and human disease modeling led to the disco- their final destination and shape both tissues and organs. axonal (blue) markers. very of the link between the Fragile X Men- Soustelle L, Trousse F, Jacques C, Ceron J, Cochard 2- Neural and glial tal Retardation protein and actin remodeling Distinct homeostatic cell interactions control directio- P, Soula C, and Giangrande A. labeling on pupal wing. Neurogenic role of Gcm transcription factors is (2003). A transgenic model of retinal dege- nality, coordination and integrity of the migratory unit. conserved in chicken spinal cord. This dynamic event can hardly be tackled in vivo in large Development. 134:625-634. (2007). neration (2005), has also been developed. Angela coordinated the imaging facility until animals. We have developed a simple model to analyze De Iaco R, Soustelle L, Kammerer M, Sorrentino S, Jacques C, Giangrande A. Huckebein mediated au- 2 2009. n the cellular and molecular features of this collective be- toregulation of Glide/ Gcm triggers glia specification. havior.< EMBO J. 25:244-254. (2006). 13 Control of endocrine cell differentiation in the pancreas and intestine An important bottleneck in the generation of beta cells from human ES cells is the inability to obtain functional, glucose responsive, insulin-secreting beta cells in vitro. For this reason, our current studies emphasize unappreciated signaling pathways and mechanisms of islet progenitor cell highlights maturation. We also generated mouse models mimicking human beta cell deficiency to determine whether mouse and human beta cells differentiate according to similar • Cell fate choice: We made the seminal disco- genetic pathways and to explore mechanisms of beta cell very that the transcription factor Neurogenin3 regeneration in the adult pancreas. (Ngn3) is the master gene controlling endocrine In the intestine we further investigate the role of cell fate choices both in the embryonic pancreas

shaping the future the shaping enteroendocrine cells/hormones in the maintenance of the

and intestine. Mice without Ngn3 lack islet and homeostasis of the intestinal epithelium and in the control of enteroendocrine cells are diabetic and die postna- nutrient absorption and energy metabolism.< tally. • Differentiation Programme: We determined the transcriptome of islet progenitors leading to Gérard Gradwohl the identification of Insm1 and Rfx6 transcription factors as two downstream effectors of Ngn3 endocrinogenic function. We reported for the Mechanisms 1 first time that Rfx6 is essential for proper islet cell of stem/progenitor cells development. differentiation probing complexity • Beta cell neogenesis: We contributed to the de- As a PhD student at the IGBMC (Strasbourg), monstration that new beta cells can arise, de novo, working on DNA repair, Gérard Gradwohl from progenitor cells in the injured adult mouse Future strategies for cell replacement therapies and rege- showed that the Zinc-finger domains of Poly pancreas. nerative medicine strongly depend on our knowledge of (ADP-ribose) polymerase detect DNA strand the detailed mechanisms that control the differentiation of breaks (1990). He then became interested in multipotent stem cells into highly specialized cells. Along • Signals: We demonstrated that retinoic acid signaling development biology and relocated as post- these lines of research, our goal is to understand how pan- is required for the normal development of the dorsal pan- doc to the Mount Sinai Hospital (Toronto, creatic and intestinal endocrine cells are generated from creas. Canada) where he studied, in 1992, TIE2, a endodermal stem/progenitor cells during embryogenesis • Enteroendocrine cells: We generated the first mouse mo- tyrosine kinase receptor that controls angio- del with a specific ablation of enteroendocrine cells and towards adult life. Pancreatic endocrine cells are clustered genesis in the mouse embryo. Gérard then discovered that enteroendocrine cells/hormones are essen- in islets within the exocrine tissue and include insulin- joined the team of Francois Guillemot at the Mellitzer, G., Beucher, A., Lobstein, V., Michel, P., tial for life and control intestinal crypt cell homeostasis as Robine S., Kedinger, M., and Gradwohl, G. Loss of en- IGBMC on the role of bHLH transcription fac- secreting beta cells that control glucose homeostasis and teroendocrine cells in mice alters lipid absorption and well as lipid absorption. n become destroyed in Type-1 diabetes. Intestinal endocrine glucose homeostasis, and impairs postnatal survival. tors in neurogenesis. cells, also called enteroendocrine cells, are closely related Journal of Clinical Investigation. 120:1708-21. (2010). In 2000, he showed that Neurogenin3, one endocrine cells, found within the intestinal epithelium, Soyer, J., Flasse, L., Raffelsberger, W., Beucher, A., of the factors studied, was also key for pan- Orvain, C., Peers, B., Ravassard, P., Vermot, J., Voz, M. which secrete a variety of hormones promoting pancreatic L., Mellitzer, G. and Gradwohl, G. Rfx6 is an Ngn3-de- creatic beta cell differentiation, a discovery pendent winged helix transcription factor required for which promoted the creation of his Inserm insulin secretion to regulate various aspects of digestion. pancreatic islet cell development. 1- Enteroendocrine progenitor cells Particularly, we focus on the role of transcription factors Development 137:203-212. (2010). (Ngn3-eYFP in yellow) in intestinal team at Hautepierre Hospital (Strasbourg). crypts of adult mouse small intestine. His group then determined that neuroge- and signals in the control of cell fate choices and the ac- Xu,X., D’Hoker,J., Stange,G., Bonne,S., De Leu,N., 2- Xiao,X., Van de,C.M., Mellitzer,G., Ling,Z., Pipeleers,D., Insulin-producing beta cells (red) in nin3 also controls endocrine fate decision in quisition of the generic and specific properties of islet and the adult mouse pancreas express Rfx6 Bouwens,L., Scharfmann,R., Gradwohl,G., and intestinal stem cells. In 2008, he joined the enteroendocrine cell during organogenesis. We hope that Heimberg,H. Beta cells can be generated from endoge- transcription factor (green nuclei). IGBMC to develop his research on the regu- our studies will contribute to the development of a cell nous progenitors in injured adult mouse pancreas. Cell. 132:197-207. (2008). lation of endocrine cell differentiation in the based therapy in diabetes, as well as to understand the Martin,M., Gallego-Llamas,J., Ribes,V., Kedinger,M., pancreas and intestine. n mechanisms underlying the pathophysiology of islet and Niederreither,K., Chambon,P., Dolle,P., and Gradwohl,G. < Dorsal pancreas agenesis in retinoic acid-deficient 2 enteroendocrine hormone failure in the human. Raldh2 mutant mice. Dev. Biol. 284:399-411. (2005).

15 Genetic and molecular analysis of early neurogenesis in Drosophila melanogaster The regulation of Achaete/Scute by Islet seems to depend on the specific enhancer context. In order to clarify how enhancer position and context can lead to different outcomes, we have developed sensors in Achaete 5’UTR that allow us to measure in vivo variations in enhancer-promoter co-ope- highlights rations. We have also identified a novel enhancer, Scutellar, that appears to mediate such variation in Achaetae/Scute expression • Our genetic screens led us to characterize se- Currently, we are exploring three mir-9 and three mir-9* pro- veral zinc finger-containing transcription factors ducts as regulators of a clock-pulsed feedback loop of Notch. (the GATA factor Pannier, the FOG homologue With the use of new tools, we are performing a unique ge- Ushaped, the LIM proteins Islet and dLMO)

shaping the future the shaping netic analysis to reveal the individual contribution and ex-

that together define the prepattern for the me- pression patterns for each mir hairpin. Similar mechanisms dian thorax. may be involved in acute leukemia and several non-Hodgkins • We have highlighted the importance of the lymphomas in human. We will perform microarray assays to Ldb homologue Chip in stabilizing enhancer- check whether specific miRNA may influence early LMO2- or promoter communications during Achaete/Scute Pascal Heitzler transcription. Moreover, we showed that dLMO Notch-dependent steps of T-cell differentiation in mouse.< acts as an activator, while Islet and Ushaped be- have as negative regulators, of the Pannier/Chip- Formal genetics as a vocation 1 dependent Achaete/Scute expression. Both Usha- Pascal Heitzler developed very early on an ped and Pannier recruit the dCtBP protein and interest for genetics. His encounter with Pat its partner HDAC1 in a repressive mechanism Simpson in 1985 confirmed his vocation and probing complexity involving alteration of local chromatin structure, Our focus is to understand how neurons are specified wi- while Islet repression seems to mediate competi- he joined her team for his PhD on the analysis of developmental genetics on sensory organ thin uniform fields of cells. We use the power of Droso- tion for Chip. patterns Drosophila (1993). Together they phila genetics to address this question. The regulation of were the first to reveal the role of Notch/Delta the two key proneural genes Achaete and Scute provide the • The main dLMO isoform, named dLMO-PA, controls as receptor/ligand during lateral inhibition. identity and the position of most of the sensory organs both neurogenesis and wing development. dLMO is ho- In 1994, he obtained a post-doc position at within the peripheral nervous system. Achaete and Scute mologous to the leukaemogenic factor LMO2 that is found in similar transcription complexes in human. We the IGBMC and revealed a feedback loop encode bHLH transcription factors, which, together with mechanism in Notch-Delta signaling. He the Zn-finger transcription factor GFI/Senseless, confer found that an ancient family of miRNAs (mir-9) regulates Heitzler P. Biodiversity and non canonical Notch si- dLMO abundance, and in turn controls neurogenesis in then discovered a genetic network, including the potential to develop a neural fate to cells. The general gnaling. In «Notch signaling». (R. Kopan, Ed),Elsevier Drosophila. Thus, as for LMO2, dLMO stoichiometry is GATA, FOG, LIM-HD, Ldb, LMO, SWI/SNF Inc., San Diego. architecture of the peripheral nervous system, also called Current Topics in Developmental n Biology. 92:427-451. (2010). critical in vivo. transcription factors which are involved prepattern, is controlled by specific transcription factors. in sensory bristle prepatterning. In 2001, These bind to enhancers common to both Achaete and Biryukova I, Asmar J, Abdesselem H & Heitzler P. Drosophila mir-9a regulates wing development via he became a team leader and described Scute which in turn promote proneural expression in small fine-tuning of LIM only factor, dLMO. the role of Chip in proneural enhancer- Dev Biol. 327:487-496. (2009). fields of cells, the proneural clusters, at reproducible an- promoter communications, as well as a new tero-posterior and dorso-lateral coordinates. The spacing Biryukova I & Heitzler P. Drosophila C-terminal non-canonical Notch pathway. His recent binding protein, dCtBP is required for sensory organ 1- MicroRNA expression in between neuron precursors is achieved by a mechanism development and sharpens a proneural transcriptio- imaginal disc. projects focus on miRNAs that control all the known as lateral inhibition, which involves the Notch renal activity of GATA factor, Pnr. 2- MicroRNA expression described processes. n Dev Biol. 323:64-75. (2008). ceptor and its ligand Delta. We recently showed that seve- in brain. ral decisions mediated by Notch and Delta are fine-tuned Asmar J, Biryukova I & Heitzler P. Drosophila dLMO- PA isoform acts as an early activator of achaete/ and controlled by a common set of microRNAs. Collecti- scute proneural expression. vely, these mechanisms define the positions and identities Dev Biol. 316:487-497. (2008). of each sensory organ; similar mechanisms are conserved Biryukova I & Heitzler P. The Drosophila LIM-Homeo- in human haematopoiesis and might be at play in the etio- domain Islet protein antagonizes proneural cell specification in the peripheral nervous system. 2 logy of T-ALL leukemia. < Dev Biol. 288:559-570. (2005). 17 In vivo analysis of cellular plasticity

in C. elegans The aim of our work is to systematically address the cellular and molecular mechanisms that allow a differentiated cell to be reprogrammed and change identity. Such knowledge has profound implications for the elaboration of therapeutic strategies, both in cancerology and in cellular therapy. highlights Many technical obstacles remain in complex organisms to address these questions in vivo, in particular because it is virtually impossible to track cells as they get reprogrammed • Cellular potential: We have found that a pulse in mammals. of Notch signal is necessary for the Y cell to ac- Our novel experimental model, combined with integrated quire the competence to switch identity. • Direct cell type conversion occurs in vivo molecular and cellular in vivo approaches allows us to by-

through distinct intermediate cellular steps, not future the shaping pass these limitations and bring new insights into cellular via a mixed cellular identity. Remarkably, Y-to- plasticity. We will focus on the mechanisms that make a PDA conversion, which occurs in the absence of specific cell, rather than its neighbors, competent to change cell division, involves as a first step the complete identity and the cellular mechanisms that are used to allow erasure of the initial identity. Importantly, this its conversion. The comparison of the mechanisms used in Sophie Jarriault dedifferentiated state has limited cellular poten- different direct reprogramming events will be key for our tial. This suggests that unlike reprogramming understanding of cellular plasticity in vivo. < Cellular plasticity and induced in vitro, natural in vivo reprogramming reprogramming in C. elegans is much more constrained. 1 • Technical development: We have developed Sophie Jarriault obtained her PhD in Alain Deep Mapping, an innovative method using Israël’s laboratory at the Pasteur Institute probing complexity next generation sequencing, which allows mu- (Paris) where she worked on the transduc- tation identification without any prior SNP tion of the Notch signal in mammals. In 1998, How differentiated cells can change their identity is a fascina- her research led to an original model for si- ting question in biology and has implications for the develop- gnal transduction involving cleavage of the ment of regenerative medicine strategies. Numerous examples knowledge. Deep Mapping is a powerful, yet a concep- Notch1 transmembrane receptor and release of cellular plasticity in physiological, experimental and patho- tually simple strategy that is easy to apply to different mo- of the intracellular part. She did her post- logical settings exist, but how a differentiated cell can change its del organisms. doc research at Columbia University (New identity remains unknown. Our research tackles this important • Impact of cell division on the cellular potential: Compa- York), where she worked with Iva Greenwald rison of reprogramming events in C. elegans suggests that question by employing a powerful and innovative model, the on vulva organogenesis in C. elegans. She different cellular strategies are used to erase the initial iden- C. elegans notably, involved the COREST corepressor nematode . tity: retraction from the tissue, which resembles an EMT, and the LSD1 demethylase in downstream We study in vivo cell reprogramming events at the single cell Zuryn S., Le Gras S., Jamet K. and Jarriault S. Deep or asymmetric cell division. n level. Specifically, we focus on a differentiated rectal cell (na- Mapping: A novel mutagen-based method for direct modulation of Notch-mediated target genes mapping and mutation identification using deep expression. med Y) that during normal development changes its identity sequencing, in Press Genetics. (2010). into a motoneuron (named PDA). We notably investigate the In 2006, she was awarded the Young Investi- Jarriault S. LIN-12/Notch signaling: Induction, lateral gator Starting Grant (ATIP-CNRS) as well as cellular and molecular events underlying Y-to -PDA cellular specification and interaction with the EGF/Ras pa- other grants from the ARC, FRM and AFM to reprogramming. Our system also allows us to identify the mo- thway. Handbook of Cell Signaling 3rd Edition (Eds. R.A. Bradshaw and E.A. Dennis). 1- Visualization of the adherens junc- start her own team at IGBMC. Sophie chose lecular players and to dissect the cellular requirements during Elsevier Academic Press. :1891-1895. (2009). tions that shape the posterior of the to focus her research on cellular plasticity. At cell type conversion in vivo. Comparing different cell plasticity worm, including the rectal area. Jarriault S.*, Schwab Y. & Greenwald I. A C. elegans 2- Electron microscopy picture of the Present, her team works on the mechanisms events, we are assessing what key aspects have been conserved model for epithelial-neuronal transdifferentiation. rectal area of a young C. elegans larva, of cellular reprogramming in C. elegans, and in cell reprogramming. PNAS, 105(10) : 3790-5 *, corresponding author. 5/3/08 « Must Read », « Top 10 Developmental showing Y cell epithelial cell. Ventral is has established the worm as a powerful ani- Biology Papers » of Faculty 1000. (2008). to the bottom. Our integrated approach will contribute to unraveling the key mal model to study such processes in a phy- mechanisms that allow a differentiated cell to become plastic Jarriault S. and Greenwald I. Functional interchangea- siological context. n and change its identity. This knowledge has significant thera- bility of ADM-4/Tace and SUP-17/Kuzbanian in C. elegans. Developmental Biology. 287(1):1-10 (2005). peutic implications, as it will further our understanding as to 2 how certain cancers arise, and will improve our ability to reprogram cells for regenerative medicine purposes. < 19 Forces and signals

in tissue morphogenesis Today, in connection with the analysis of cell shape changes and secretion, my lab is focusing on the input of physical forces in morphogenesis. My view is that physics is at the crossroads of cell and developmental biology, and will provide major input to interpret key biological processes. It highlights offers very important perspectives for the decade to come. More generally, we are reaching a point where quantitative • Cell polarity: We previously analysed genes that analysis and modelling is becoming essential in biology. maintain epithelial polarity and adherens junc- To accomplish this, in the coming years, we will progress tion integrity. along two axes: ● Analyze the role of forces in epithelial morphogenesis, • Forces in morphogenesis: We identified several shaping the future the shaping including their input on trafficking

pathways that control myosin II activity and ● Study how osmotic pressure affects membrane tension found that myosin II is mainly active in a subset and lumen shape.< of cells. Modelling in collaboration with physicists has confirmed our genetic data. Michel Labouesse • Hemidesmosomes (HDs): We have contributed to define the nature of HD-like junctions Through epithelial cell 1 between the epidermis and the ECM and revealed how the spectraplakin VAB-10 maintains differentiation epidermal integrity against mechanical stress Having an engineering degree in maths probing complexity during morphogenesis. More recently, we could and physics from Ecole Polytechnique, identify proteins that promote HD biogenesis Michel Labouesse began a career in biology Our team’s research is based on the interface of cell and de- and found that HDs provide a platform for me- and obtained his PhD in genetics in Piotr velopmental biology, focusing on epithelial tissues, which chanotransduction during morphogenesis. Slonimski’s laboratory (Gif-sur-Yvette, 1983). form the architecture of most of our organs. These highly His work dealt with the control of polarized cells that have specific junctional complexes, • Trafficking: We characterized the first transmembrane mitochondrial gene expression by nuclear complex acting in apical trafficking. By doing so, we play an essential role during embryonic morphogenesis, as genes. Inspired by Sydney Brenner’s work well as later on in physiology. showed that apical secretion of some protein cargos involves the release of exosomes from multivesicular bodies, on the nematode C. elegans, he decided The goal of our research is to explain how embryos form which is mediated by the V0 sector of the V-ATPase. to switch to this model in 1989 during his and grow to generate organs with different properties and postdoc at MIT. shapes. We are dissecting the processes that create a lumen, Zahreddine H*, Zhang H*, Diogon M, Nagamatsu Y, Labouesse M. CRT-1/calreticulin and the E3-ligase EEL-1/ • New technique: We designed a protocol to easily bridge Supervised by H. Robert Horvitz, he was secrete specific proteins to distinct surfaces, or bring cell HUWE1 control hemidesmosome maturation in C. time-lapse imaging with electron microscopy (CLEM). n initially interested in understanding how two shape changes. Many organs include several cell types of elegans development. Curr. Biol. 20:322-327. (* co-first) (2010). cells become different during asymmetric epithelial and non-epithelial origins; an important focus of cell division. The Zn-finger transcription Gally C, Wissler F, Zahreddine H, Quintin S, Landmann our studies is to understand how these cells interact with F, Labouesse M. Myosin II regulation during C. elegans factor LIN-26 that characterized turned out each other to achieve higher order tissue morphogenesis. embryonic elongation: LET-502/ROCK, MRCK-1 and PAK- to be essential for the differentiation of 1, three kinases with different roles. In parallel, we intend to use the knowledge gained from 1- Closing the gap between fast the entire skin. Michel began his research Development. 136:3109-19. (Issue cover). (2009). fluorescence videomicroscopy and studies in embryos to reveal the causes of pathologies in- at IGBMC in 1992 and went on to work Ciarletta, P., Ben Amar, M., and Labouesse, M. Conti- high resolution electron microscopy volving structures, such as the hemidesmosome, that are nuum model of epithelial morphogenesis during C. through Correlative Light and on epithelial morphogenesis. Today, he present in C. elegans and mammals. elegans embryonic elongation. Electron Microscopy. leads the Development and Stem Cells Philos Transact A Math Phys Eng Sci. 367:3379-400. 2- A 4-colour view of the main We are mainly using the model C. elegans, combining C. Programme. n (2009). elegans hemidesmosome compo- molecular genetics and modern imaging methods to Liégeois, S., Benedetto, A,, Garnier, J.M., Schwab, Y. and nents and underlying muscles. capitalize on the speed of development and simplicity of Labouesse, M. The V0 ATPase mediates apical secretion < of Hedgehog-related proteins through exosomes. 2 this system. J. Cell Biol. 173:949-961. (rated Must Read by F1000). (2006).

21 Retinoic acid signalling pathways driving stem spermatogonia ontogenesis and differentiation The seminiferous epithelium comprises somatic, supporting, Sertoli cells that contribute to the niche environment directing the fate of spermatogonia. Outside their niche, spermatogonia can become multipotent and therefore represent possible tools highlights for cellular therapy. We propose to identify the genetic networks and to characterize the molecular mechanisms through • Two distinct, sequential, sources of RA involved which RA, notably in Sertoli cells, controls sperma- in spermatogonia differentiation. RA synthesized togonia proliferation and differentiation. Our pre- by somatic Sertoli cells is indispensable only du- liminary data indicate that expression of the few ring the prepubertal wave of spermatogenesis. future the haping s genes known to be involved in stem spermatogonia

The subsequent differentiation of spermatogo- homeostasis is not altered upon impairment of RA nia requires RA synthesized by their progenies, function. Thus, RA acts on yet uncovered genetic the meiotic spermatocytes, a mechanism which cascades, the understanding of which will open Manuel Mark might be instrumental to the perpetuation of the new perspectives on stem cells with promising the- spermatogenetic cycle. Norbert Ghyselinck rapeutic potential.< • A catabolic barrier protects spermatogonia from untimely differentiation. The peritubular myoid At the face of Molecular cells that surround the seminiferous epithelium Genetics and Developmental 1 isolate spermatogonia from extratubular sources Biology of RA through synthesizing the RA-degrading enzymes, CYP26. Mark Manuel obtained an MD degree from probing complexity • A model of non-canonical mechanism of action Strasbourg University and defended his PhD for RAR. As the pathological phenotypes resul- in 1988 on extracellular matrix functions Retinoic acid (RA), the biologically active metabolite of vi- during embryonic development. After tamin A, exerts a wide range of cellular effects by regulating joining Pierre Chambon’s team in 1992 he proliferation, differentiation and apoptosis. At the cellular ting from the ablation of RAR and of RXR in Sertoli cells became involved in the phenotypic analysis level, the action of RA is controlled through the modulated are really different, the canonic RAR:RXR heterodimers of Hox gene mutant mice. In 1993 he initiated expression of cellular enzymes producing or degrading RA, do not operate in these cells. This probably also applies to collaboration with Norbert Ghyselinck who retinaldehyde dehydrogenases (RALDH) or cytochrome spermatogonia. was also a member of Chambon’s team. • P450 hydroxylases (CYP26), respectively. Then, acting in A novel switch which controls the choice between mitosis Norbert Ghyselinck received his PhD in and meiosis. STRA8 protein is involved in the process that an hormone-like manner, RA binds to nuclear receptors 1991 from Clermont-Ferrand University. His leads to stable commitment of differentiated spermatogo- research focused on the regulation of gene (RAR) that function as transcriptional regulators through Mascrez B, Ghyselinck NB, Chambon P, Mark M. A nia to the meiotic cell cycle. n controlling, usually in the form of heterodimers with rexi- transcriptionally silent RXRalpha supports early em- expression by nuclear receptors. In 2004 he bryonic morphogenesis and heart development. was appointed a Research Director of the noid receptors (RXR), the expression of RA target genes. Proc. Natl. Acad. Sci. USA. 106:4272-4277. (2009). Among the various tissues whose physiology depends upon CNRS. Mark M, Jacobs H, Oulad-Abdelghani M, Dennefeld C, Together, Mark and Ghyselinck formed a vitamin A action, the seminiferous epithelium of the testis Féret B, Vernet N, Codreanu CA, Chambon P, Ghy- selinck NB. STRA8-deficient spermatocytes initiate, team at IGBMC to decipher retinoic acid represents the most remarkable paradigm to investigate the 1- but fail to complete, meiosis and undergo premature Immunostaining of spread signaling pathways during differentiation pleiotropic effects of RA in vivo, as it integrates the pro- chromosome condensation. nuclei to visualize chromosomes blematic of stem cell renewal, cell proliferation, switching J. Cell Sci. 121:3233-3242. (2008). during meiosis of male stem cells. In 2006, they brought to 2- light non-canonic mechanisms of actions for from mitotic to meiotic cell division, programmed cell Vernet N, Dennefeld C, Guillou F, Chambon P, Ghy- Histological section showing selinck NB, Mark M. Prepubertal testis development pathological accumulation retinoic acid receptors in vivo. n death and paracrine signaling. Using a combination of relies on retinoic acid but not rexinoid receptors in of lipids in the seminiferous innovative genetic, pharmacological and molecular ap- Sertoli cells. EMBO J. 25:5816-5825. (2006). epithelium proaches in the mouse, we are studying the cellular and Mark M, Ghyselinck NB, Chambon P. Function of molecular mechanisms that underlie the capabilities of RA retinoid nuclear receptors: lessons from genetic and pharmacological dissections of the retinoic acid signa- to promote spermatogonia differentiation and beyond the ling pathway during mouse embryogenesis. differentiation of normal stem cellsin vivo.< Annu. Rev. Pharmacol. Toxicol. 46:451-480. (2006). 2 23 Development of muscle and vertebrae My lab is now trying to understand the mechanisms controlling axis formation and patterning at the genomic level. We have set out to identify the gene regulatory networks involved in these processes focusing on the molecular highlights basis of the oscillator controlling segment production and on the control of differentiation of the muscle and vertebral lineages. Our work now relies more and more on • Segmentation clock : We have identified a mo- quantitative approaches and modeling at the interface with lecular oscillator associated with the process of physics. rhythmic production of vertebral precursors In parallel, we are developing in vitro systems of these in the embryo. The pulsatile signal generated

shaping the future the shaping processes using embryonic or reprogrammed stem cells,

by the oscillator travels progressively along the with the goal of using these systems to shape strategies embryo thus generating the spatial periodicity for therapeutical approaches of diseases of the musculo- of the future vertebrae. This led us to propose a skeletal axis.< comprehensive paradigm accounting for vertebrate segmentation. • Axis elongation : We have shown the role of Olivier Pourquié Hox genes in the collinear control of mesoder- All about embryo patterning 1 mal cell ingression and proposed a mechanism akin to diffusion involving a gradient of random Olivier Pourquié graduated as an engineer cell motility to explain the striking terminal from the National Institute of Agronomy and elongation process resulting in body formation completed his PhD and postdoc work in de- probing complexity in the embryo. velopmental biology with Nicole le Douarin We are interested in the mechanisms controlling the for- • Bilateral symmetry : We have demonstrated that a novel pathway downstream of retinoic acid is at the College de France. mation of the body of vertebrates during embryogenesis. In 1996, he became an independent group In particular, we have been focusing on the process of axis leader at the Institut de Biologie du Déve- elongation and on segmentation whereby a periodic se- required to buffer the desynchronizing effect of the left- loppement de Marseille (IDBM). There, he ries of anatomical structures such as vertebrae are formed right machinery which controls the asymmetrical deve- published the first evidence of a molecular lopment of organs such as heart or liver. This mechanism during organogenesis. Our work relies on developmental oscillator which controls segmentation of maintains the bilateral symmetry of cervical somites. biology studies in chicken, mouse and zebrafish embryos the vertebral precursors, the segmentation • Segment number : We have identified a mechanism in- combining genetic approaches with genomic strategies volved in the control of vertebral number and have de- clock. This discovery was acknowledged as such as transcriptomics or high throughput sequencing Bénazéraf, B., Francois, P., Baker, R.E., Denans, N., monstrated that in snakes, acceleration of the segmenta- one of the 24 milestones in developmental and bioinformatics as well as sophisticated in vivo ima- Little, C.D., & Pourquié, O., A random cell motility tion clock accounts for the increase in vertebral count. n biology over the past 100 years by the ma- gradient downstream of FGF controls elongation of gazine ging. Our goal is to understand the basic principles under- an amniote embryo Nature. in press (2010). Nature. lying these morphogenetic processes. We are actively col- In 2002, he joined the Stowers Institute for Vilhais-Neto, G.C., Maruhashi, M., Smith, K.T., laborating with physicists and mathematicians to attempt Vasseur-Cognet, M., Peterson, A.S., Workman, J.L., Medical Research (US) and became a Ho- to model these complex molecular and cellular processes & Pourquie, O., Rere controls retinoic acid signalling ward Hughes Medical Institute Investiga- and somite bilateral symmetry. 1- Somite organization highlighting tor in 2005. In 2009, he returned to France in the embryo. Nature. 463(7283):953-957 (2010). the actin-rich apical side of epithelial Equally we are interested in the clinical relevance of these and became the director of the IGBMC. His Gomez C, Ozbudak EM, Wunderlich J, Baumann D, cells (green), nucleus (blue), basal side findings and are exploring the molecular basis of spine Lewis J & Pourquié O. (2008). Control of Segment (red). research is focused on the development of patterning defects such as scoliosis in humans. Lastly, we number in vertebrate embryos. 2- Segmental gene expression in muscle and vertebrae, using in vivo strate- Nature. 454(7202):335-9. (2008). embryo. HN-Cadherin (green), actin are moving into the field of regenerative medicine, trans- gies such as mouse genetics and microsur- Dequeant, M.L., Glynn, E., Gaudenz, K., Wahl, M., (red), nucleus (blue). Dorsal view. gery or in vitro approaches based on em- lating our understanding of differentiation of the muscle Chen, J., Mushegian, A., & Pourquie, O., A complex bryonic stem cells. n and vertebral lineages into in vitro strategies to differenti- oscillating network of signaling genes underlies the mouse segmentation clock. ate mouse and human embryonic or reprogrammed stem Science. 314(5805):1595-1598 (2006). cells for cellular therapies of degenerative diseases such as 2 Duchenne muscular dystrophy. < 25 Laboratory of Our research is articulated around three axes : ● Rectification of individual cells’ motion : By using surface Cell Physics patterning, we are seeking to show that the directed motion of cells can be a physical mechanism with no chemical gra- dients. Some synthetic molecules targeted against the actin cytoskeleton are also tested in collaboration with the laboratory of J.-M. Lehn at ISIS. highlights ● Dynamics of monolayer : We are studying the evolution of cells monolayer under the microscope and in silico; we translate images of contacts into local constraints in order • Collective effects in vitro: We showed an insta- to explain and predict the changes in local and global shapes bility of molecular motors by developing a new

shaping the future the shaping of cells monolayers. Extensions for this project address the

acto-myosin motility assay. The filaments go distributions of constraints within developing embryos with spontaneously back and forth, which suggests an oscillatory mechanism at play in cells. several groups at IGBMC, in particular the teams of O. Pour- quié and M. Labouesse. • Mechanosensing in cell adhesion: We demonstra- ● Cell division : We are characterizing the closure of the cyto- ted that focal contacts and cell-cell contacts are kinetic ring in a chemical physics way by using a new method undergoing elongation upon force application. of observation, combining microfabrication, genetics, and This reinforcement mechanism explains key as- optical observations. A technology transfer based on our Daniel Riveline pects of cell motility and tissue organisation. new method is being developed for a new high-throughput screening device for anti-cancer drugs.< Physics to explain roles of 1 • Soft Matter Physics for Cells: We developed molecular motors in biology quantitative models for explaining the shapes of adhesive contacts and the shapes of yeast cells. Daniel Riveline graduated with a master’s probing complexity The geometrical relations are derived from phy- degree in physics and then received a PhD Cells are traditionally viewed as a soup of chemical reac- sical laws demonstrated in soft matter systems. at the Curie Institute (Paris). He focused on tions. However cell shape is also the result of self-assembly actin-myosin molecular motors with J. Prost and A. Ott and in 1997 he revealed the os- phenomena; the physical laws of matter provide the ap- cillatory nature of these motors. Next he ob- propriate framework for understanding shapes of cells and • The cytokinetic ring closure: By developing a new ap- tained a post-doc position at the Weizmann tissues. Within the cells, the cytoskeleton dynamics and proach, we outlined a mechanism for explaining the clo- Institute (Israel) with A. Bershadsky where its associated Rho pathways give the proper unit for un- sure of the cytokinetic ring in fission yeast. The action of n he was trained in cellular biology and stu- derstanding cell motility, cell division and cell shapes wi- molecular motors promotes the ring closure. died cell adherence to the extracellular ma- thin tissues. We use interdisciplinary approaches to address trix. these phenomena in cell culture. The physical framework In 1999, he created his own group in cellular is inspired from soft matter physics. The biological side adhesion and the structure of chromosomes. is adapted from cell biology for changing specifically cell Demonstrating cell mechanosensory mecha- shapes with cytoskeleton drugs, genetic modifications, Riveline D., P. Nurse, Injecting yeast, Nature Methods. 6:513. (2009). nisms for focal contacts and intercellular and mechanical constraints. The chemical part consists contacts. A sabbatical in P. Nurse’s team at Riveline D. Explaining lengths and shapes of yeast by in designing new agents for altering cell motility and cell the Rockefeller University followed where scaling arguments. 1- Reinforcement in cells. Cells division. In the long term, our research may provide new PLoS One. 4(7):e6205. (2009). he focused on cytokinetic ring closure and probe their environment by ideas for understanding cancer. Brevier J, Montero D, Svitkina T, Riveline D. pulling on adhesion areas. developed a new method to observe this Being interdisciplinary in nature, our group is located both The asymmetric self-assembly mechanism of adhe- 2- Microfabrication and Biology. process. rens junctions: a cellular push-pull unit. at The Science and Supramolecular Engineering Institute By imposing the location of In 2009, he created the Laboratory of Cell Phys Biol. 5(1):016005. (2008). individual yeast cells, we can study in Strasbourg for the physical/chemical themes as well as Physics, a joint laboratory between the Ins- Brevier J., M. Vallade, D. Riveline, Force-extension self-assembly mechanisms and at the IGBMC for those of cell biology. We use classical relationship of cell-cell contacts, develop new methods such as the titut de science d’ingénierie supramolécu- Phys. Rev. Lett. 98:268101. (2007) n cell lines for fibroblasts and epithelium, along with fission 2 first yeast injection shown here. laires (ISIS) and the IGBMC. yeast as a model system for cytokinesis. Microfabrication plays a key role for our measurements of forces, as well as for ordering cells in our experiments.< 27 Epigenetics and cell fate in early mammalian development The proteins that regulate chromatin structure in the early embryo, or the way in which the chromatin is remodeled throughout preimplantation development are largely unknown. Our efforts during the coming years will be devoted to understand : highlights ● how the structure of the chromatin is established at the beginning of embryonic development and how it supports totipotency. ● which players are involved in chromatin remodeling during • Reprogramming: early mammalian development. In an effort to delve into the mechanisms gover- ● the role of these molecules in reprogramming and in

ning epigenetic reprogramming, we have iden- future the shaping formation of the pluripotent compartment of the inner cell

tified new histone modifications and uncovered mass.< putative roles for histone variants in this process.

• Cell fate: We have determined that by manipulating the epigenetic information of a cell we can regulate Maria Elena Torres-Padilla its fate. We also revealed that histone modifications, in particular arginine methylation, can re- Epigenetics in cellular 1 gulate pluripotency in the early mouse embryo. differentiation

• Fertility: In 2002, Maria Elena Torres-Padilla obtained probing complexity By using genetic approaches, we have shown her PhD at the Pasteur Institute (Paris) on the role of the nuclear receptor HNF4 in hepatic Research in our group focuses on understanding how early that a protein related to the TATA-binding differentiation. Notably, she demonstrated mouse development is regulated by chromatin-mediated the role of chromatin factors on the specific changes in gene regulation, that is, by epigenetic informa- action of splicing variants of HNF4. An inte- protein, TBP2, is essential for female fertility and oocyte tion. In particular, we are interested in understanding how rest in chromatin led Marie-Elena to become the transitions in cell potency and cell fate are regulated by growth. TBP2 plays its part by regulating the transcriptional Programme of the oocyte as well as chromatin conden- focused on its study in early development chromatin-mediated processes. We use the mouse embryo sation. n transitions. She did post-doctorate research as a model because this is one of the few systems where it at the Gurdon Institute (Cambridge Univer- is possible to explore the foundations of totipotency and sity, UK) with Magdalena Zernicka-Goetz in differentiation. Indeed, the zygote, which is the product Gazdag E1. Santenard A1. Ziegler-Birling C. Altobelli close collaboration with Tony Kouzarides. G. Poch O. Tora L* Torres-Padilla ME* TBP2 is essen- of fertilization of an oocyte by sperm, has an inherent ca- tial for germ cell development by regulating trans- They were able to show that cell fate and pacity to form all cell types in an organism. Chromatin- cription and chromatin condensation in the oocyte. pluripotency are controlled by epigenetic in- Genes and Development. 23(18):2210-23. (2009). mediated changes in gene regulation have to ensure the 1Equal contribution. *Corresponding authors. formation in the early embryo. plasticity required for undertaking such an essential task At the end of 2006, Maria Elena Torres-Padilla Daujat S, Weiss T, Mohn F, Lange U. C, Ziegler-Birling during development. C, Zeissler U, Lappe M, Schübeler D, Torres-Padilla joined Laszlo Tora’s team, noted for its bio- 1- Mouse blastocyst a day be- Our projects will help us to understand how chroma- ME, Schneider R. H3K64 trimethylation marks he- chemical approach on the analysis of trans- terochromatin and is dynamically remodeled during fore implantation. Blue DNA, tin structure is progressively modified to restrict cell fate developmental reprogramming. yellow cell-cell boundary. crition mechanisms, to expand her bioche- determination with the consequent loss of totipotency. Nature Structural Molecular Biology; 16(7):777-81. 2- Male and female pronuclei mical skills. At the end of 2008, she created (2009). Our work will also allow new insights in understanding undergoing the first mitosis. her own team at the IGBMC on epigenetic the biology of the pluripotent stem cells, in particular on Santenard A. Torres-Padilla ME. Epigenetic reprogram- mechanisms in early mouse development. n ming in mammalian reproduction: contribution from their origin and development. From a broader perspective, histone variants. Epigenetics. 4(2):80-84. (2009). 2 deciphering the basic mechanisms underlying the earliest Torres-Padilla ME. Parfitt D.E. Kouzarides T. and steps of mammalian development is essential to unders- Zernicka-Goetz M. Histone arginine methylation tand early aspects of embryonic development, human re- regulates pluripotency in the early mouse embryo. Nature. 445(7124):214-218 (2007). production and stem cell biology. < 29 Mecano-genetic interplays and embryonic morphogenesis We aim at investigating the relationship between the viscous forces generated by blood flow and endothelial tissue organization. Endothelial cells express different genes in response to the flow patterns they experience. Our working hypothesis is that blood flow influences highlights cardiovascular development by acting on cell identity and cell motility.

• Addressing the dynamics of development: the car- We generated a flow responsive reporter in order to explore diovascular system is under the influence of com- endothelial cell responses to shear forces during embryonic plex stimuli generated by flowing blood. We iden- blood vessel development. This line will allow us to address

tified the physical stimuli involved in controlling future the shaping precisely the flow-tissue interaction during vascular

valvulogenesis during heart development and development and to address the endothelial cell behavior in found a flow responsive gene linking blood flow response to flow using live imaging. and valve morphogenesis • Mixing classical approaches in genetics with light We use molecular biology and genetic approaches to imaging to address cilia activity during development: address the gene networks activated by blood flow.< Julien Vermot We discovered that manipulating cilia dynamics using mRNA knock down affects inner ear for- 1 mation. The use of fast imaging uncovered the Fluid dynamics applied to mechanism of action of cilia during this process development • Developing approaches to probe flow in vivo:We In 2003, Julien Vermot completed his PhD used techniques to measure flow and explored with P. Dollé at the IGBMC in development probing complexity cilia mediated flow in the embryo. In particular, we used fast imaging combined with optical biology and genetics. In 2004, he became During embryonic development, cells act as force sensors a member of O. Pourquié’s team at The and can actively trigger physical changes in order to main- Stowers Institute for Medical Research in Kansas City, USA to supplement his PhD tain the harmonious body-plan patterning and growth. approaches to analyze cilia mediated flow in the left-right work. Next, he joined the group of S. Fra- Defects in these processes can cause catastrophic develop- organizer and in the developing inner ear ser at the Beckman Imaging Center of the mental abnormalities, in particular in the cardiovascular • Using multidisciplinary approaches to address embryogene- California Institute of Technology (Pasadena, system where blood flow is generating shear forces essen- sis: In collaboration with physicists, engineers and mathematicians, we proposed new models, approaches and hy- USA) as a long term HFSP fellow in 2005. tial for cardiogenesis. pothesis to solve problems related to flow. n This experience allowed him to become fa- We use live imaging techniques, cell biology and genetic miliar with a broad range of live imaging analysis to study the dynamics and the roles of biologi- techniques that he would employ to address cal flow during the development of the zebrafish and the Vermot J, Forouhar AS, Liebling M, Wu D, Plummer the role of cilia driven flow and blood flows Danio rerio. Our goals are to address the physical stimuli D, Gharib M, Fraser SE. Reversing blood flows act during embryogenesis. and the molecular/genetic mechanisms that specify cell through klf2a to ensure normal valvulogenesis in the developing heart. Julian notably demonstrated the role of bio- responses to flow forces during embryogenesis. In parti- PLoS Biol. e1000246. 7(11) (2009). logical flow produced by cilia in inner ear 1- Intersegmental vessels and cular, we are interested in understanding the relationship development, as well as the importance of Colantonio JR*, Vermot J*, Wu D, Langenbacher their flow dynamics revealed between physical forces and tissue organization during en- AD, Fraser S, Chen JN, Hill KL. The dynein regulatory by a transgenic line labeling red reversing flow during heart valve formation complex is required for ciliary motility and otolith dothelium maturation. biogenesis in the inner ear. (*equal authors). blood cell (red) and endothelial (2009). The accumulation of is research expe- Also, we investigate how cells alter and maintain their phy- Nature. 457:205-9. (2009). cell response (white). rience offered new prospects and he retur- 2- Head vascular network in the sical environment to control morphogenesis. To address ned to France in 2009 to create his own team Supatto W, E. Fraser S, and Vermot J. An all-optical Zebrafish embryo labeled using this question, we study the activity of beating cilia during method for probing microscopic flows in living tis- the fli:gfp line. in the IGBMC, where he focuses on the role sues. Biophysical J. 95(4):L29-31. (2008). embryogenesis using novel imaging techniques to visualize of fluid forces on embryogenesis. n and analyze cilia mediated flow.< Vermot J, Fraser SE, Liebling M. Fast fluorescence 2 microscopy for imaging embryonic development. HFSP journal. 2:143-155. (2008).

31 Primordial germ

cells’ (PGC) ontogeny Being responsible for the in vitro fertilization ward of the hospital, we believe that it is of fundamental importance to conduct research as a continuum from basic to clinical and from clinical to basic. In this context, we hope that our work will highlight some of the fundamental mechanisms highlights in the PGC’s ontogeny, contribute to the understanding of pluripotency and will have a clinical outcome. Indeed, the study of genes involved in such processes will • PGC’s ontogeny: we have identified a new gene notably clarify the biology of PGC and pluripotency but should Tex19.1 specifically expressed by PGC and plu- allow significant advances in the production of pluripotent ripotent stem cells, that is essential for the for- stem cells that can be used either as cellular models to mation of male gametes. The protein presents study the physiopathology of diseases or as a tool for cell two well conserved domains of unknown func- future the shaping therapeutic, or for pharmaceutical screening. tion. We also aim to produce cellular models for the research • Pluripotency: Starting from the human ES cell model, we have recently cloned a gene coding community by building a biobank of iPS cells. < for a specific pluripotent stem cell protease, which is also expressed by germ cells. Stéphane Viville • Genetics of infertility: Studying two families, we have cloned two genes involved in the for- Primordial germ cells, first 1 mation of the acrosome. We are now analyzing a step in reproductive biology third family with brothers suffering from azoos- probing complexity permia. After Stéphane Viville received a degree in Pharmacy, he completed his PhD in immune Primordial germ cells (PGC) represent a unique class of • Pathological models: We have generated the se- tolerence with Diane Mathis and Christophe cells. They are the embryonic precursors of the gametes, cond largest (worldwide), collection of human Benoist’s team in Strasbourg. In 1993, he ensuring propagation of the gene pool to the next gene- demonstrated the fundamental role of the ration and the continuation and evolution of the species. invariant chain. Stéphane undertook his embryonic stem cells carrying genetic disease genes. In Our main focus is to decipher the molecular mechanisms post-doc research with Azim Surani’s team that account for maintenance of their pluripotency. In- addition, we have implemented the reprogramming technology and produced dozens of iPS cells from normal or in Cambridge, (UK) and working on genomic deed, PGC’s can be considered as totipotent cells since pathological tissues. n imprinting, proved the role of PEG1 in mater- following fertilization they can generate all cell types and nal behavior. In 1995, he created the Preim- yield a fully functional organism. plantation Genetic Diagnosis Center at the Accordingly, most if not all, pluripotent genes are ex- P Tropel, J Tournois, J Côme, C Varela, C Moutou, P Fragner, M Cailleret, Y Laâbi, M Peschanski, S Viville Strasbourg Hospital and also taught classes pressed by PGCs. Our goal is to identify actors involved High efficiency derivation of human embryonic stem at the Faculty of Medicine while working on cell lines following pre-implantation genetic diagnosis. in the process of the PGC’s ontogeny, to study their phy- In Vitro Cellular & Developmental Biology– Animal retinoic acid with Manuel Mark’s group. siological functions and to challenge them as pluripotency 2010 46(3-4):376-85. Epub Mar 9. (2010). In 2003, he formed his own team at the reprogramming factors. Madanl B, Madanl V, Weber O, Tropel P, Bluml C, Kief- IGBMC, focusing on primordial germ cell We also study the genetics of infertility in humans. Spe- fer E, Viville S, Fehling HJ. The strictly pluripotency- ontogeny. In 2008, his team identified a new associated gene Dppa4 is dispensable for embryonic 1- Immunofluorescence detection cifically, we aim to identify genes affecting human game- stem cell identity and germ cell development, but gene involved in pluripotency (Tex19) and a of Oct4 (red) or Tex19.1 (green) and essential for embryogenesis. human mutation that influences acrosome togenesis and therefore potentially being involved on the Mol. Cell. Biol. 29(11):3186-203. (2009). merge image. Top at 8 cells stage, PGC’s ontogeny. Based on our expertise in mouse and bottom at blastocyst stage. development (SPATA16). Since 2004, he has Kuntz S, Kieffer E, Bianchetti L, Lamoureux N, Fuhr- 2- In situ hybridization detecting human embryonic stem (ES) cells, we are setting up a new mann G, Viville S. Tex19, a mammalian specific pro- led the Reproductive Biology Ward at the tein, with a restricted expression in pluripotent stem Tex19.1 mRNA on male (top) or Strasbourg Hospital. n platform dedicated to the production of pluripotent stem cells and germ line. Stem Cells 26: 734-744. (2008). female embryonic gonads (bottom). cells, such as ES or induced pluripotent stem (iPS) cells. Dam AHDM, Koscinski I, Kremer JAM, Moutou C, This is done in parallel with the creation of a Biobank of Jaeger A-S, Oudakker AR, Tournaye H, Charlet N, < Lagier-Tourenne C, van Bokhoven H, Viville S. Homo- 2 human somatic cells that serve as pathological models. zygous mutation in SPATA16 is associated with male infertility in human globozoospermia. Am. J. Hum. Genet. 81:813-820. (2007). 33 Regulation of gene expression, signalling and cancer

" The idea is to study in the widest sense the transcription control, in normal, physiological but also pathological states ". I. Davidson

The fundamental mechanisms regulating gene ex- mones and metabolites and of their cofactors is the pression have been one of the major research areas second major theme of the Programme. The func- of the IGBMC, and its forerunner the LGME, for tion of several receptors, principally estrogen, glu- more than 30 years. Since the initial purification cocorticoid, vitamin D3 and retinoic acid receptors and characterization of RNA polymerase II by Pierre in development, physiology and disease are studied Chambon and colleagues, a consistent theme has by germ line and spatio-temporal somatic mutation been the identification of the machinery required for in an extensive set of recombinant mouse models. basal and regulated transcription. The isolation of In recent years, this approach has revealed the im- two major transcription factors TFIIH and TFIID portance of retinoic acid signaling in the develop- proved a major advance in understanding the close ment of hepatocellular link between transcription, DNA repair and human carcinoma, and vitamin 13 Groups disease and highlighted the importance of the prei- D signaling in atopic nitiation complex in developmental and cell-specific dermatitis and asthma. 32 Staff Scientists gene regulation. Currently, the Programme has in- Complementary to the 42 Postdoctoral fellows corporated the study of epigenetics and chromatin in vivo studies are the 53 PhD students dynamics, RNA metabolism as well as high through- biochemical charac- put genomic and proteomics technologies as it pur- terization of receptor 34 Engineers/Technicians sues its quest to understand the regulation of gene cofactors and the mole- expression. cular basis of cross-talk 1 Assistant The study of nuclear receptors, transcription factors with other signalling whose activity is regulated by a diverse set of hor- pathways. A recurrent and transversal theme throughout the Programme is how the normal gene regulatory me-

• Fundamental mechanisms of transcription, RNA metabolism and DNA chanisms are deregulated during malignant transfor- repair : identification and characterisation of complexes involved in trans- mation. The Programme has underlined the contri- cription, RNA degradation and DNA repair, role of nuclear and cellular organisation in the control of these processes. bution of basal factors, transactivators, epigenetics and nuclear receptors in the etiology and treatment • Epigenetic modifications, histone variants and chromatin dynamics during differentation : purification and characterization of complexes involved of various cancers. Bringing together the teams Functional in the enzymatic modification of histones and deposition of histone va- working on functional genomics and on cancer in riants in chromatin, role of these factors in control of gene expression in differentiation and development. one Programme aims to strengthen the interaction around this common theme. The recruitment of Genomics & • Physiopathology and molecular biology of nuclear receptors : development of mouse models for study of nuclear receptors and their cofactors new groups in epigenetics, nuclear organization and in metabolism and disease, identification and characterisation of nuclear receptor cofactor complexes, high throughput genomic approaches to DNA repair underscores the commitment of the Cancer identify target genes and pathways. Programme to pursue the study of the links between n • Signalling pathways, gene expression and cancer : integrative ap- fundamental nuclear processes and cancer. proaches to link basal factors, DNA repair, nuclear receptors and other transcription regulatory factors and signalling pathways to deregulated gene expression involved in malignant transformation, development of novel paradigms for cancer therapy through targeting epigenetic enzymes, understanding the basis of tumor-cell selective apoptosis. Human cancers : molecular characterisation of factors overexpressed in breast and other human cancers, discovery, and testing of novel prognostic markers and therapeutics.

35 Hematopoiesis and

Leukemogenesis in the Mouse Today we are dissecting the molecular pathways regulated by the Ikaros family. We will apply this knowledge and our tools to understand how Ikaros family members control hematopoietic cell differentiation, stem cell function and highlights chromatin remodeling. We are using the Ikaros-deficient T-ALL model to address fundamental issues regarding T-cell • Cancer: Using genetic approaches, we have de- leukemogenesis, such as the existence and veloped a mutant mouse line (IkL/L) in which identity of leukemia initiating cells and the role Ikaros expression is knocked down to 10% of of the Notch receptors. <

normal levels. We have shown that Ikaros exerts future the haping its tumor suppressor activity by repressing the transcription of target genes associated with the s Notch pathway in developing T cells. Notch ac- Philippe Kastner tivation is therefore an early and critical event during T-cell leukemogenesis in IkL/L mice. Susan Chan Moreover, we have provided evidence that the 1 Ikaros gene is mutated in human T-ALLs. Two converging careers

• Hematopoiesis: In the B-cell lineage, we have Susan Chan obtained her Bachelor’s degree probing complexity shown that Ikaros blocks the development of immature pro/preB cells in the bone marrow at the University of California, Berkeley and Hematopoiesis is characterized by the development of and controls isotype selection during class switch her PhD in immunology at the University of hematopoietic stem cells into pluripotent progenitor recombination in mature splenic B cells. In the Pennsylvania in the U.S. In 1991, she moved dendritic cell (DC) lineage, we have shown that cells and finally into mature blood cells. This orderly and to Strasbourg to study T-cell differentiation as Ikaros is specifically required for the differentia- continuous process involves self-renewal, cell fate choice, a post-doctoral fellow with Diane Mathis and differentiation and proliferation. Transcription factors are tion of a subset of DCs called plasmacytoid dendritic cells. Christophe Benoist. There, she met Philippe responsible for coordinating these processes but their Kastner, a scientist in Pierre Chambon’s expression must be tightly regulated to prevent hematolo- • Ikaros family members: More recently, we have generated gical malignancies. In this context, we are interested in the the first knock-out mouse line for Helios (Ikzf2), another lab. A graduate of Ecole Polytechnique, he member of the Ikaros family. We are currently investiga- following questions. was working at the time on retinoic acid ting how Helios plays a role in hematopoiesis. n How do transcription factors control hematopoiesis ? A Marçais, R Jeannet, L Hernandez, J Soulier, F receptors and developing mutant mouse How do alterations in their function contribute to leuke- Sigaux, S Chan and P Kastner. Genetic inactivation of models to study their function. In 1997, they Ikaros is a rare event in human T-ALL. mogenesis ? Leukemia Res. 4:426-429. (2010). started a new team together at the IGBMC. In the past, we have shown that retinoic acid receptor Q Cai, A Dierich, M Oulad-Abdelghani, S Chan and P Now they study how transcription factors alpha and PU.1 play important roles in granulocyte and Kastner. Helios deficiency has minimal impact on T regulate hematopoiesis and how mutations erythroid differentiation, respectively. Our current studies cell development and function. J Immunol. 183:2303-2311. (2009). in these proteins promote leukemia focus on the Ikaros family of transcription factors, which M Sellars, B Reina-San-Martin, P Kastner and S development. n act mainly as transcriptional repressors through associa- Chan. Ikaros controls isotype selection during class tion with chromatin remodeling complexes. Ikaros (Ikzf1) switch recombination. J Exp Med. 206:1073-1087. (2009). 1- Specific gene expression signatures define various is a zinc finger protein expressed by all hematopoietic subtypes of murine T-cell leukemias. cells. Ikaros is crucial for lymphocyte differentiation and E Kleinmann, AS Geimer Le Lay, M Sellars, P Kastner 2- Activation of Notch1 transcription from an intragenic and S Chan. Ikaros represses the transcriptional promoter in Ikaros-deficient T-cell leukemias: visuali- homeostasis and also functions as a tumor suppressor in response to Notch signaling in T-cell development. 2 Mol Cell Biol. 28:7465-7475. (2008). zation by ChIP-seq of histone H3 acetylation over the T and B cells. Furthermore, loss of Ikaros has been detec- Notch1 gene in IkL/L tumors with an intact Notch1 gene ted in human T- and B-cell acute lymphoblastic leukemias (black) or with a deletion of the Notch1 promoter (red). (ALLs). The molecular mechanisms responsible for these activities remain unclear.< 37 Structure and function of the general

transcription factor TFIID The development of high-throughput genomic technologies (ChIP-seq, RNA-seq) facilitates the characterization of complex gene regulatory networks. We are using these approaches to address the functions of transcription factors such as MITF, its co-factors and target gene products highlights in the proliferation of malignant melanoma, the TEAD family in muscle differentiation and regeneration and the RARs and RAR-regulated transcription factors in neuronal • The TAF4 subunit of transcription factor differentiation of ES cells and tumor suppression. TFIID plays an important role in diverse si- We are also pursuing our characterization of TAF4 through gnaling pathways as an essential co-activator for the generation of novel tissue-specific knockout mice. We CREB and the RARs. Genetic study of TAF4- have identified a novel TAF4-containing TFIID sub-complex

null MEFs and its inactivation in the mouse future the shaping that is abundant in several cell types and are investigating epidermis revealed novel functions in regulating its potential function by comparing the genomic occupancy the TGF-beta and EGF signaling pathways and of TAF4 and TBP in these cells. < highlighted its role as a cell autonomous and cell non-autonomous tumor suppressor. Irwin Davidson • We characterized the molecular basis of the Regulation of transcription cross-talk between the RA and TGF-beta signa- in differentiation and cancer 1 ling pathways in MEFs. RA induces TGF-beta dependent autocrine growth by directly activa- After obtaining his PhD at the University of Glasgow ting the expression of the TGF-beta3 ligand and on the herpes virus (1985), Irwin Davidson became probing complexity the secreted mitogen connective tissue growth The main focus of our work over the last several years factor (CTGF). Transient RA treatment is suffi- a post-doc fellow with Pierre Chambon’s group in has been to understand the role of TFIID subunits such cient to set up a positive feedback loop between Strasbourg, working on the identification of trans- as TAF4 or paralogues such as TAF4b, TRF2 or TAF7L these two mitogens. cription factors interacting with the SV40 enhancer. in gene expression. The study of TAF4 function in cells • We used ChIP-chip and transcriptomics/RNA-seq to In 1990, he became interested in the mechanisms derived from genetically modified mice in vitro and tis- identify RAR binding sites and target genes in MEFs and responsible for transcription activation and in 1993 sue-specific knockouts in vivo revealed novel facets of its ES cells. More than 750 RAR-occupied promoters were he participated in the identification of the TFIID fac- identified, in which the vast majority were cell specifically function as a regulator of multiple signaling pathways and tor and its role as a co-activator. Irwin then focused occupied. Our results reveal that differences in the chro- cell proliferation, as well as a tumor suppressor. The study on cloning genes and encoding different TFIID sub- Delacroix L, Moutier E, Altobelli G, Legras S, Poch matin landscape regulate accessibility of RARs to their of TAF4 as a co-activator for the retinoic acid receptors O, Choukrallah M-A, Bertin I, Jost B, and Davidson target loci modulating the repertoire of target genes that units through biochemical, structural and genetic (RARs), allowed us to decipher the molecular mechanism I. Cell-specific interaction of retinoic acid receptors n approaches. He also discovered the important role with target genes in mouse embryonic fibroblasts can be regulated and the biological effects of RA. of cross-talk between the RA and TGF-beta signaling pa- and embryonic stem cells. of the histone fold motif in TFIID organization. At Mol. Cell Biol. 30: 231-244. (2010). thways that promotes cell proliferation. We completed this the beginning of 2000, he began to study the role of cycle of experiments by using ChIP-chip to identify RAR Fadloun, A., Kobi, D., Delacroix, L., Dembélé, D., TBP and its paralogue TRF2 in the mouse, where he Michel, I., Lardenois, A., Tisserand, J., Losson, R., occupied loci and to target genes revealing the importance Mengus, G., and Davidson, I. Retinoic acid induces 1- Mislocalisation of H1T2 demonstrated the specific role of TRF2, in transcrip- of cell-specific binding site occupancy in determining the TGFb-dependent autocrine fibroblast growth.Onco - in TRF2-null mouse haploid tion regulation in male germ cells. gene. 27(4):477-89. (2008). biological response to RA. spermatids. 2- Senescent human 501 mela- This work also led to the discovery of novel histone More recently, we were responsible for setting up high Fadloun, A., Kobi, D., Pointud, J-C., Kumar, I., Teletin, M., Bole-Feysot, C., Testoni, B., Mantovani, R., noma cells. variants and chromatin-associated proteins that throughput sequencing techniques at the IGBMC. The Metzger, D., Mengus, G., and Davidson, I. The TFIID specify nuclear domains within the developing sper- implementation of these technologies has profoundly alte- subunit TAF4 regulates keratinocyte proliferation and has cell-autonomous and non-cell-autonomous matozoa. Irwin’s group characterized the structure red our experimental Programme over the last few years al- tumour suppressor activity in mouse epidermis. and functions of the TFIID subunit TAF4 and revealed lowing us to ask different sets of questions. We have begun Development. 134(16):2947-58. (2007). its role in various signaling pathways. n to use these techniques to understand the role of various 2 transcription factors in developmental and pathological processes. < 39 Genome expression

We aim to: and repair ● better understand the mechanisms of gene expression and DNA repair and to elucidate the dynamic interactions between these two pathways. ● explain the biochemical phenotypes of transcription/ repair syndromes, focusing on the hormonal dys-regu- highlights lation that leads to these various phenotypes. In addition, it will allow us to gain extensive insights into the physiology of nuclear hormones. • Over the last five years we have dissected the ● employ sophisticated technologies to obtain mecha- role of each of the TFIIH subunits and explained nistic details on DNA repair. These include : the molecular defects in transcription and repair - Screening of genomic siRNA libraries to identify responsible for the phenotypes of XP and TTD new DNA repair factors

patients mutated in TFIIH subunits. We have future the shaping - Follow up TTD/XPD diseases in vivo in animal mo- recently identified the tenth subunit of TFIIH dels using a robotic biopsy collection and Computed and demonstrated its specific involvement in Tomography (CT) coupled with 3-D tissue reconstruc- Frédéric Coin DNA repair; mutation in this subunit results tion in collaboration with IRCAD (Strasbourg). in TTD group A disorder. We showed that the ● further our understanding of molecular effects in- Jean-Marc Egly CAK module was not part of TFIIH when reduced by anti-cancer agents, in collaboration with a moving DNA lesions but was specifically devo- pharmaceutical company.< Transcribing and ted to the transcription function of TFIIH. repairing DNA. • In transcription, we showed that CAK was 1 not only involved in the phosphorylation of the Educated in biochemistry, Jean-Marc Egly RNA polymerase II but also in the phospho- became interested in two main cellular rylation of several nuclear receptors e.g. retinoic mechanisms, DNA transcription and repair. probing complexity acid, peroxisome proliferator-activated and thy- Besides their fundamental character, his works roid hormone receptors. The phosphorylation Transcription, one of the key steps of gene expression in contributed to many breakthroughs for the response to different stimuli of the organism like stress or comprehension of cancerogenesis and rare of these nuclear receptors by TFIIH is required for their hormones, requires a combination of factors. The deleterious genetic disorder mechanisms. In 1985, he recruitment and stabilization to their DNA cognate se- action of physical or chemical agents that create lesions in the started his team in Strasbourg. In 2006, he quence, leading to the ligand-dependent transactivation was appointed president of the ARC scientific DNA disrupts the expression of genes. If these lesions are not of their responsive genes. Mutation in XPD subunit of council and, in 2007, special advisor for the removed by efficient repair systems they will be at the origin TFIIH (as found in XP-D patients) destabilize the inte- general director of Inserm. of mutations that can lead to cancer and aging. TFIIH, a raction between the CAK complex and the core TFIIH, Frédéric Coin was a PhD student in Jean- multi-subunit complex that we are studying plays a pivotal leading to nuclear receptor phosphorylation defect and n Marc Egly’s team and revealed in 1998 that role in both the transcription of genes and their repair. Ueda, T., Compe, E., Catez, P., Kraemer, K.H., impaired transactivation of specific genes. and Egly, J.M. Both XPD alleles contribute to the mutations on helicases XPD and XPB observed Mutations in some of the subunits of TFIIH are responsible phenotype of compound heterozygote xeroderma pigmentosum patients. in Xeroderma pigmentosum affected the for three genetic diseases (xeroderma pigmentosum (XP), tri- J Exp Med. 206:3031-3046. (2009). transcriptional function of TFIIH. In 2004 chotyodystrophy (TTD) and Cockayne syndrome (CS)), Coin, F., Oksenych, V., Mocquet, V., Groh, S., Blattner, Frédéric isolated the 10th subunit of TFIIH the phenotypes of which result from defects in both DNA C., and Egly, J.M. Nucleotide excision repair driven involved in trichothiodystrophy (TTD). Their by the dissociation of CAK from TFIIH. 1- Coomassie blue stai- repair and gene expression. For instance, TTD patients pre- work then continued on the link between Mol Cell. 31:9-20. (2008). ning of the highly purified sent brittle hairs and nails, that cannot account from a defect nucleotide excision repair genome expression and repair. The team also in DNA repair and that can be recapitulated in mouse TTD Compe, E., Malerba, M., Soler, L., Marescaux, J., Borrelli, E., and Egly, J.M. Neurological defects in (NER) factors required to showed TFIIH factor implication in Rift valley models. With the help of biochemical, genetic and cellular trichothiodystrophy reveal a coactivator function of remove DNA damages. viral infection in collaboration with the Pasteur TFIIH. Nat Neurosci. 10:1414-1422. (2007). 2- Transactivation me- biology we study these diseases and consequences of dere- Institute. n chanism mediated by the gulation of gene expression and repair in various cellular sys- Coin, F., De Santis, L.P., Nardo, T., Zlobinskaya, O., phosphorylation of nuclear Stefanini, M., and Egly, J.M. p8/TTD-A as a Repair- tems and animal models.< Specific TFIIH Subunit.Mol Cell. 21:215-226. (2006) receptors by TFIIH.

41 From nuclear receptor action to novel paradigms for cancer therapy action

We will expand our bioinformatics competence to facilitate large-scale data analyses from genome-wide studies, which is an inevitable component of future biomedical research. By such global analyses we will identify sub-routines and key networks in a given programme, such as estrogens or highlights retinoic acid signaling, integrating the (epigenetic) action of, and crosstalk between co-regulators. We will decrypt the molecular and structural features underlying the tumor-selectivity of the TRAIL pathway. There • Nuclear receptor ligand action: Identification of the structural and mechanistic basis of ligand is no doubt that an understanding of this evolutionarily action, including agonists, inverse agonists, and developed tumor defence system will lead to an entirely neutral, partial and full antagonists novel class of cancer therapeutics, devoid of the (geno) shaping the future the shaping toxicity of current chemo/radiotherapy. • Description of the mechanistic basis and We will continue using our expertise to generate novel (epi-) cancer therapeutic potential of two apoptoge- drugs for improved cancer therapies.< nic rexinoid-based therapeutic paradigms. This Hinrich Gronemeyer work allows for the preparation of clinical studies. Towards novel anticancer therapies 1 • Identification of the convergence of several Chemist by training, Hinrich Gronemeyer divergent cancer therapeutics, including probing complexity retinoids and HDAC inhibitors, on the TRAIL developed a strong interest in nuclear re- pathway. ceptor (NR) signaling during his PhD studies Our interest is to understand the mechanisms of signal on the chromatin-regulatory functions of the transduction and epigenetic (de)regulation in normal cells steroid hormone ecdysone, using a photo- and cancer, which are relevant for the development of novel chemical approach. In 1980, he joined Pierre therapeutic paradigms. Based on our expertise on nuclear • Discovery of the first triple-action epi-drug (patented) Chambon’s team in Strasbourg as a post-doc receptors we first develop global systems biology approaches for cancer therapy and demonstration of strong anticancer fellow, where he purified and contributed to to deconvolve receptor signaling complexity and aberrant activity and drug action in tumor cells of animal models cloning of the progesterone and glucocorti- (epigenetic), signaling upon tumorigenic transformation treated in vivo. coid receptors. and study the mechanisms and therapeutic potential of can- After two years at the Ludwig Institute for • Discovery of the crosstalk between histone Cancer Research, Hinrich returned to Stras- cer-selective apoptosis pathways induced by various signa- acetyltransferases and methyltransferase CARM1, which bourg to start his own group. In 1989 he ling drugs and epigenetic modulators. Our studies involve Pavet, V., Beyrath, J., Pardin, C., Morizot, A., Lechner, specifies estrogen sub-programmes and is altered during predicted the existence of NR co-regulators a plethora of genome-wide technologies and the correspon- M.C., Briand, J.P., Wendland, M, Maison. W., Fournel, n S., Micheau, O., Guichard, G. and Gronemeyer, H. breast cancer progression. and in 1996 he cloned TIF2 and established ding development of bioinformatics tools. (2010). Multivalent DR5-selective peptides activate the first 3D structures of a ligand-binding do- One emphasis of our work is to decipher the mechanisms the TRAIL death pathway and exert tumoricidal activity in vivo. Cancer Res. 70:1101-10. (2010). main with Dino Moras. Thereafter, Hinrich’s underlying the cancer-selectivity of apoptogenic TRAIL work has focused increasingly on thera- signaling. We use the obtained knowledge to devise novel Germain, P., Gaudon, C., Pogenberg, V., Sanglier, S., Van Dorsselaer, A., Royer, C.A., Lazar, MA., Bourguet, 1-MS275 induces apoptosis in the peutic applications, discovering in 2001 the therapeutic tools and study the contribution of this pathway W. & Gronemeyer, H. (2009). Differential action on blasts of individuals with acute myeloid TRAIL connection. In collaboration with che- coregulator interaction defines inverse retinoid ago- to the action of (epi-) drugs. Studies on the role of the senes- nists and neutral antagonists. leukemia. mists and the pharmaceutical industry, his cence-mediated secretome on TRAIL action and the epige- Chemistry & Biology. 16:479-89. (2009). 2- Epigenetic information provided by chromatin modifications and team developed several novel therapeutic netic alterations during cellular senescence address the link Shankaranarayanan, P., Rossin, A., Khanwalkar, H., non-coding RNAs contributes to paradigms. Since 2005, Hinrich is the coor- between cancer and aging. Jacobson, A., de Lera, A. R., Altucci, L., and Grone- transcriptional regulation and genomic dinator of the Epigenetic Treatment of Neo- meyer, H. (2009). Growth factor-antagonized rexinoid Our work benefits from the integration and coordination of apoptosis involves permissive PPAR /RXR heterodi- architecture. plastic Disease (EPITRON) consortium. n mers to activate the intrinsic death pathway by NO. several national and European consortia, which provide the Cancer Cell. 16:220-31 (2009). necessary multidisciplinary input and a close link to the local hospital (HUS). < 2 43 Chromatin and epigenetic regulation Our major goal is to study the epigenetic mechanisms underlying gene regulation using mammalian cells as a model system. More specifically, we are interested in addressing how histone variants are deposited at specific chromatin loci and how this impacts chromatin structure highlights and gene regulation. We are also interested in the role of non-coding RNA in histone deposition. The involvement of non-coding RNAs • Chromatin remodeling: in targeting molecules adds another level of complexity We discovered the molecular mechanism of to chromatin regulation. Interestingly, histone variants chromatin remodeling by drosophila NURF. deposition complexes contain several non-coding RNAs. NURF remodels chromatin by sliding nucleo- However, the mechanism by which these RNAs function is

somes along DNA. future the shaping unknown. One of our future aims will be to elucidate how these interactions influence histone deposition and gene • Gene regulation: regulation.< We have shown that the histone variant macroH2A directly binds PARP-1 and inacti- vates transcription by down-regulating PARP-1 Ali Hamiche enzymatic activity. A chromatin biochemist 1 • Histone deposition: We have identified and characterized the first Ali Hamiche graduated from the Pierre and probing complexity vertebrate histone chaperone, involved in the Marie Curie University (Paris VI), where deposition of CenpA at centromeres. he also obtained a PhD on chromatin The main research activity of our group is to study the role We have investigated in detail the molecular structure and function. Recruited in 1996 as of histone variants and their deposition machineries in the mechanism of the histone variant H3.3 depo- a Research Scientist with Hélène Richard- sition and found that the death-associated pro- epigenetic control of human genome activity at the genome- Foy’s team (LBME, Toulouse), he worked wide level. tein DAXX and the chromatin-remodeling factor ATRX on conformational transitions of the Among the various epigenetic memory mechanisms, the lo- are crucial components of the H3.3 deposition machinery. nucleosome during transcription. cal replacement of canonical histones within the nucleosome Our data argues that DAXX functions as a histone chape- In 1998 he received a Human Frontier post- by variant histones has the potential to affect considerably rone, involved in the replication-independent deposition doctoral fellowship and joined Carl Wu’s the activity of the corresponding genomic regions. Indeed, of H3.3, thus linking apoptosis to gene regulation. Our laboratory at the National Cancer Institute, findings also provide a clue as to how mutations in the nucleosomes bearing histone variants have distinct structures (NIH) in Bethesda, MD, US. ATRX gene lead to the human genetic diseases of a-tha- In 1999 he discovered the mechanism of and functional activities in vitro and some histone variants Drané P, Ouararhni K, Depaux A, Shuaib M and lassemia and X-linked mental retardation. n n are incorporated at specific genomic locations. Our labora- Hamiche A. The death-associated protein DAXX is a chromatin remodeling by the Drosophila novel histone chaperone involved in the replication- NURF complex . In 2003, he joined the André tory is focusing on the role of histone variants in gene re- independent deposition of H3.3. gulation and genome integrity. We have recently implicated Genes Dev. 24(12):1253-65. (2010). Lwoff Institute (Villejuif) as a young group leader to work on histone variants, and two macroH2A in PARP-1 enzymatic activity and transcription Shuaib M, Ouararhni K, Dimitrov S and Hamiche A, regulation (Ouararhni et al., 2006), and discovered a new (2010). HJURP Binds CENP-A via a highly conser- years later he joined the IGBMC to create ved N-terminal domain and mediates its deposi- 1- Specific marking of chromatin a new team that currently focuses on the link between histone variants, transcription factors and non- tion at centromeres. Proc. Natl. Acad. Sci. USA. by histone variants. 107(4):1349-54. (2010). same topic. n coding RNA (unpublished results). This association with 2- Schematic representation of transcription factors and non-coding RNA is novel and will Ouararhni K, Hadj-Slimane R, Ait-Si-Ali S, Robin P, the assembly of the core histones Mietton F, Harel-Bellan A, Dimitrov S, Hamiche A. The into the nucleosome. certainly help us to understand how chromatin domains are histone variant mH2A1.1 interferes with transcrip- established and how epigenetic information is stored and tion by down-regulating PARP-1 enzymatic activity. Genes Dev. 20(23):3324-36. (2006). transmitted to daughter cells. Alteration of these epigenetic marks is associated with developmental disorders and cancer. < 2 45 Genetic dissection of nuclear receptor Our projects are aimed at further characterizing the physiological role of nuclear receptors, the mechanism signaling in the mouse of their action at the molecular, cellular and organismal levels, and their implication in the pathogenesis of human diseases. We will analyze in skeletal muscles the functional role of AR, GR and PPARs, and of some of their co-regulators (SRC-1, TIF2 and SRC-3; NCoR and highlights SMRT), in order to characterize the signaling pathways controlled by these factors and to identify new drug targets to prevent or treat metabolic and muscle diseases. The role played by TSLP and nuclear receptors • Through phenotypic analyses of various mouse in the pathogenesis of atopic dermatitis and asthma mutants, we have revealed that RXR/RAR and will be further investigated, as well as their function in haping the future the haping RXR/VDR heterodimers, as well as GR, control intestinal epithelial cells, where they could be involved

the expression of the cytokine “thymic stromal s in the control of the immune response to commensal lymphopoietin (TSLP)” in epidermal keratino- bacteria. This latter study and related studies should cytes, and demonstrated that this cytokine plays reveal some of the molecular mechanisms through which the dialog between the microbiota and intestinal a key role in initiating the development of a skin Pierre Chambon and systemic disease mimicking human atopic epithelial cells contributes to homeostasis and disease of the intestine. < dermatitis. Daniel Metzger • Our studies also revealed that enhanced TSLP expression in mouse epidermal keratinocytes ag- All about nuclear receptors gravates experimental allergic asthma, indicating Pierre Chambon was ranked fourth among 1 that keratinocyte-produced TSLP may represent most prominent life scientists for the 1983- an important factor in the “atopic march” that 2002 period. Honorary Professor at the Collège links atopic dermatitis and asthma. de France and Emeritus Professor at the Facul- probing complexity • By analyzing mutant mice in which PPARβ is té de Médecine, he was the founder and first selectively ablated in skeletal muscles, we have Director of the IGBMC and the Institut Clinique The last decade has seen an enormous rise in the interest demonstrated that this nuclear receptor is instru- de la Souris (ICS). for nuclear receptors (NRs), because of their central role During his PhD training performed under in the coordination of development and homeostasis, mental in myocytes to the maintenance of oxidative fibers, Pierre Chambon’s supervision, Daniel Metzger through their ability to transduce hormonal signals into and have shown that fiber type switching is likely to be the revealed a striking conservation of the molecu- modulation of gene activity. Our main goal is to study, un- cause, and not the consequence of metabolic diseases such lar mechanisms underlying transcriptional ac- as obesity and diabetes. der physiological and pathophysiological conditions in the tivation across eukaryotes. He was recruited in • By ablating the tumor suppressor gene PTEN selectively whole organism, the function and interdependence of si- 1995 at the CNRS, and established CreERT2, an in epithelial cells of the mouse prostate, we have generated gnaling pathways that are regulated by various nuclear re- a model mimicking human invasive prostatic adenocarci- efficient system to perform spatio-temporally ceptors [e.g. the retinoid X receptors (RXRs), the retinoic Z. Zhang, P. Hener, N. Frossard, S. Kato, D. Metzger, noma. n controlled targeted somatic mutagenesis in acid receptors (RARs), the peroxisome proliferator-activa- M. Li and P. Chambon Thymic stromal lymphopoietin the mouse, which is now used worldwide. Da- overproduced by keratinocytes in mouse skin aggra- ted receptors (PPARs), the vitamin D3 receptor (VDR), vates experimental asthma. Proc. Natl. Acad. Sci. niel then applied this mouse mutagenesis sys- the oestrogen receptors (ERs), the androgen receptor (AR) U.S.A. 106:1536-1541. (2009). tem to investigate the role of nuclear receptors and the glucocorticoid receptor (GR)] in different organs C. K. Ratnacaram, M. Télétin, M. Jiang, X. Meng, in vivo. These studies brought major insight on (e.g. skin, lung, intestine, skeletal muscle and reproduc- P. Chambon and D. Metzger. Temporally-controlled the functions of nuclear receptors, notably in ablation of PTEN in adult mouse prostate epithelium 1- Immunohistochemical detection generates a model of invasive prostatic adenocarci- intermediary metabolism and skeletal muscle. tive organs). In that respect, we have used our site-directed of RyR1 (Green) and DHPRβ (red) in noma. Proc. Natl. Acad. Sci. U. S. A. 105:2521-2526. He is presently co-leading with Pierre Cham- cell-specific temporally-controlled somatic mutagenesis (2008). mouse tibialis muscle. Nuclei are stained method, which allows the generation of somatic mutations with DAPI (blue). bon a research group on functions of nuclear M. Schuler, F. Ali, C. Chambon, D. Duteil, J-M. Bor- 2- in the mouse of any given gene, at any chosen time and Immunohistochemical detection receptors in homeostasis and diseases. n nert, A. Tardivel, B. Desvergne, W. Wahli, P. Chambon of TSLP in mouse epidermal keratino- in any specific cell type. Interestingly, as this genetic tool and D. Metzger PGC1α expression is controlled in skeletal muscles by PPARβ, whose ablation results cytes. is also of great value to generate mouse models of human in fiber type switching, obesity and type 2 diabetes. cancers, the knowledge gained from their analyses should Cell Metabolism 4:407-414. (2006). contribute to the development of new cancer therapies. < 2 47 Molecular biology of B cells SHM and CSR are initiated by programmed DNA damage induced by AID. This type of damage is normally restricted to antibody genes. However, aberrant targeting of AID to nonimmunoglobulin genes and/or abnormal repair of AID induced lesions may account for the increased propensity highlights for malignant transformation in B cells. Our projects will provide insight into the molecular mechanisms that control AID activity and that enforce the • The DNA damage sensors Parp1 and Parp2 accurate repair of AID‐induced DNA damage. Furthermore contribute to the resolution of AID‐induced they will allow us to further understand the complex DNA breaks during CSR by facilitating DNA problem of double stranded DNA break detection, signaling repair by the alternative‐NHEJ pathway and by and repair. The conclusions drawn from these projects

suppressing oncogenic translocations. future the shaping will not only foster our future studies on B cell repertoire diversification, but will also have important implications for • The transcription factor Ikaros plays a key role the fields of DNA repair and cancer.< in establishing a transcriptional competition between switch regions in individual cells that is critical for isotype specification during CSR. Bernardo Reina B cell diversification and 1 • AID associates with KAP1 and HP1 in a com- humoral immunity plex that is tethered in vivo to transcribed switch regions bearing the H3K9me3 mark. These Bernardo Reina obtained a PhD in Immu- probing complexity results provide a novel and original AID targe- nology at the Pasteur Institute (Paris). There The functional properties of antibodies are shaped during ting mechanism that accounts for the epigenetic he revealed that Trypanosoma cruzi (etiolo- gical agent of Chagas’ Disease) produces a immune responses through somatic hypermutation (SHM) modifications induced at the immunoglobulin heavy chain locus during CSR. B cell mitogen that enhances the suscepti- and class switch recombination (CSR). SHM modifies bility of the host and proposed a novel and antibody affinity, while CSR modulates antibody effector alternative vaccination strategy that can be functions by replacing the antibody isotype expressed. These • We have developed an innovative tool that allows us to generalized to other pathogens of medical reactions are unusual among somatic cells in that they are homogeneously induce double stranded DNA breaks at a single genomic locus of known sequence, and for the first importance (2000). Bernardo then reloca- initiated by DNA damage and both have been implicated time, to isolate and identify novel factors recruited into ted to New York, USA for a postdoctoral stay in the development of cancer. They are triggered by Activa- DNA repair foci. n with Michel Nussenzweig at the Rockfeller tion Induced Cytidine Deaminase (AID), an enzyme that University and the Howard Hughes Medi- deaminates cytidine residues in DNA. B lymphocytes are cal Institute (HHMI) and began working on Robert, I., Dantzer, F. and Reina‐San‐Martin, B. Parp1 facili- particularly prone to malignant transformation and it has tates alternative NHEJ, whereas Parp2 suppresses IgH/c‐ somatic hypermutation (SHM) and class been proposed that DNA damage incurred during CSR or myc translocations during immunoglobulin class switch switch recombination (CSR), two mecha- recombination. J Exp Med. 206:1047‐56. (2009). SHM may account for this cancer susceptibility. Such da- nisms initiated by Activation Induced cyti- mage might be due to bystander gene targeting by AID or Sellars, M., Reina‐San‐Martin, B., Kastner, P. and Chan, S. dine Deaminase (AID), which are essential Ikaros controls isotype selection alternatively to aberrant DNA repair. AID has the potential during immunoglobulin class switch recombination. 1- Histological section of a lymph for establishing highly specific and adapted to inflict significant collateral DNA damage. Nevertheless, J Exp Med. 206:1073‐87. (2009). node showing germinal centers, the humoral responses. He implicated the DNA sites of B cell receptor diversification most B cells expressing AID do not suffer widespread mu- Robbiani, D.F., Bothmer, A., Callen, E., Reina‐San‐Martin, damage response pathway in the mecha- by SHM and CSR. B., Dorsed, Y., Difilippantonio, S., Bolland, D.J., Chen, H.T., nism of CSR (2001) and proposed that its tation or chromosome instability and only a few non‐im- Corcoran, A.E., Nussenzweig, A. and Nussenzweig, M.C. 2- Collateral damage to the genome munoglobulin genes are known to be mutated. Therefore, AID is required for the chromosomal breaks in c‐myc that triggered by AID expression. role is to induce chromatin conformational lead to c‐myc/IgH translocations. changes that facilitate long-range recombi- it appears that specific regulatory mechanisms restrict this Cell. 135:1028‐38. (2008). potential to the appropriate cell type and loci. Despite great nation (2003-2005). In 2006, he created his Reina‐San‐Martin, B., Chen, J., Nussenzweig, A. and own group at the IGBMC. n progress, how specific AID targeting is achieved in vivo and Nussenzweig, M.C. Enhanced intraswitch region recombi- how AID‐induced DNA damage is accurately repaired is not nation during immunoglobulin class switch recombination in 53BP1‐/‐ B cells. Eur J Immunol. 37:235‐9. (2007). known.< 2 49 Molecular and cellular biology We study breast cancer via the functional characterisation of selected genes and pathways. Obesity is a of breast cancer poor prognosis factor. We have shown a connection between MMP11, cancer progression and adipose tissue. We are investigating the molecular mechanisms behind MMP11 action on cancer-associated- adipocytes (CAAs). TFF1, alias pS2, is a secreted fac- highlights tor. Despite being a classic ER-induced gene, its role in breast cancers remains unclear. We are exploring the molecular basis of TFF1 function. HER2-positive breast cancer, usually classified as high risk, is har- • Cancer and metabolism: We have identified dly a homogeneous disease. Indeed, some patients

MMP11 as an unusual matrix metalloproteinase future the haping do not experience relapse, and HER2-targeted the- that favors cancer cell invasion through the repro- s rapies show variable response. TRAF4, MLN51 and gramming of cancer-associated adipocytes (CAAs) STARD3 are overexpressed in HER2-positive tumors. towards fibroblast-like cells. Their molecular functions in normal and malignant conditions are under examination. They may help to • Cancer and mRNA metabolism: We have cha- define HER2-positive tumor subsets. Altogether, our Catherine Tomasetto racterized the RNA binding protein MLN51 as a studies will reveal targets and molecular pathways member of the exon junction complex (EJC) that that will help to understand the natural history of Marie-Christine Rio 1 controls gene expression at the mRNA level, and breast cancer and will be translated into the clinic. < showed that MLN51 is essential for the survival of probing complexity cells under stress. Development & progression of breast cancer The natural history of breast cancer involves progression • Cell polarity: We have demonstrated that the through clinical stages starting with abnormal epithelial pro- TRAF4 adaptor protein is essential during develop- Catherine Tomasetto met Marie-Christine Rio liferation, progressing into in situ and invasive carcinomas, ment and acts in epithelial cells as a tight junction- in 1989 while she was a PhD student in Pierre concluding in metastatic disease. The progression from in situ Chambon’s laboratory. Marie-Christine had to invasive carcinoma is a critical step in terms of prognosis and conducted clinical research for developing associated dynamic signaling component. tests for hormonal receptor dosage in prostate relies on cancer and normal cells present in the tumor. In this cancer at the Strasbourg Hospital. She had context, MMP11 identification as a secreted mesenchymal fac- • Translational research: Recently, in collaboration with worked since 1982, on pS2/TFF1, a marker for tor associated with invasive breast cancer was a pioneer finding the Breast Clinical Center in Strasbourg, we showed that breast cancer hormonodependence. In 1990, in the field of invasion. Using a variety of cellular and mouse hormone-dependency is underestimated in pregnancy-as- the team demonstrated the role of Matrix models of tumorigenesis, MMP11 expression by stromal cells sociated breast cancers and should be considered for patient management. n Metalloproteinase 11 (MMP11), a paracrin was shown to be crucial in the invasive process. Moreover, pro- factor synthesized by normal stromal cells gnostic studies indicated its association with a poor patient out- into the tumor. The same year, Catherine went come. Indeed, the Oncotype DX (Genomic Health, Redwood to the Dana-Farber Cancer Institute in Boston, City, CA) that predict breast cancer relapse includes MMP11 US for a post-doc position. She focused on dosage. Tumor necrosis factor receptor-associated factor 4 a tumor suppressor for breast cancer and is a dynamic tight junction-related shuttle protein in- Breast cancer is a heterogeneous disease that is currently clas- volved in epithelium homeostasis. Kédinger V, Alpy F, used subtractive hybridization screening. In sified into 3 main classes: luminal (estrogen receptor (ER) and Baguet A, Polette M, Stoll I, Chenard MP, Tomasetto 1993, she returned to Marie-Christine’s team C, Rio MC. PLoS One. 3(10):e3518; (2008). 1- progesterone receptor (PR) positive), HER2 (a member of Transverse section of a hu- and applied this technology to patient tumor man mammary gland normal the epidermal growth factor (EGF) receptor family) positive Matrix metalloproteinase-11/stromelysin-3 exhibits biopsies. collagenolytic function against collagen VI under lobule showing honeycomb and basal-like, which is primarily PR, ER and HER2 nega- normal and malignant conditions. Motrescu ER, tight junction structure with Currently, they lead a team together at tive (ie, triple negative). By comparing benign and malignant Blaise S, Etique N, Messaddeq N, Chenard MP, Stoll TRAF4 (green) co-localizing the IGBMC and are interested in tumor I, Tomasetto C, Rio MC. with occludin (red) breast biopsies, we have identified several genes including pS2/ Oncogene. 27(49):6347-55. (2008). development and progression. n .2- X-ray computed tomogra- TFF1 expressed in luminal tumors and TRAF4, MLN51 and The exon-junction-complex-component metastatic phy (microCT) of metastasis STARD3 which are specifically expressed in HER2 tumors. All lymph node 51 functions in stress-granule assembly. development (green) in the Baguet A, Degot S, Cougot N, Bertrand E, Chenard lungs of live mouse. of these genes are expressed by cancer cells and our research is MP, Wendling C, Kessler P, Le Hir H, Rio MC, Toma- focused on the function of the respective proteins. < setto C. J Cell Sci. 120(Pt 16):2774-84. (2007). 2

51 Nuclear retinoic acid receptors phosphorylation

and cross-talk with signaling pathways The importance of RARs phosphorylation stands in contrast to the difficulty of detecting this modification and of analyzing its biological significance. The challenge in the next years to come is to combine cellular, molecular, biophysical and computer modeling approaches to investigate : highlights ● the phosphorylation state of RARs in different cell types. The purpose is to correlate aberrant RAR phosphorylation states with cancer • Retinoic acid induces the rapid activation of ● the conformational changes induced by phosphorylation the p38MAPK/MSK1 pathway through non in order to predict changes in the interaction of RARs with genomic effects. Subsequently, RARs become protein partners or DNA phosphorylated at two residues through a coor- ● the role of RARs phosphorylation during development by

dinated cascade starting with the phosphoryla- future the shaping using induced pluripotent stem cells obtained from mouse tion by MSK1 of a serine located in the ligand- embryonic fibroblasts and reexpressing RARs mutated at binding domain. This phosphorylation increases the phosphorylation sites in a RAR null background. < the ability of RARs to interact with the cdk7/cy- clinH subcomplex of TFIIH with a downstream consequence on the phosphorylation of a serine Cécile Rochette-Egly located in an N-terminal proline-rich motif. From cellular • Phosphorylation regulates the transcription of to molecular biology RAR-target genes via the control of RARs re- After earning a diploma in Pharmacy and 1 cruitment to gene promoters and via RARs ubi- completing her residency in Paris, Cécile quitination and degradation by the proteasome. Rochette-Egly obtained a PhD in Cell probing complexity Biology in Villejuif in 1978. At that time her work dealt with cell signaling and cyclic We work at the interface of cellular and molecular biology nucleotide second messengers. In 1979 she focusing on retinoic acid, the active metabolite of vitamin • New coregulators with SH3 domains and interacting joined Inserm as a Research Associate and A, which controls cell proliferation and differentiation with the N-terminal proline-rich motif have been cloned in 1980 she obtained a Honorary Doctorate through nuclear receptors. These receptors, RARs, work and shown to interact with RARs in a phosphorylation- of Science on the role of cyclic nucleotide dependent manner. as ligand-dependent transcriptional regulators but com- in biological functions. In 1988, she joined plexity came with the finding that RARs are targets for Pierre Chambon’s team in Strasbourg to post-translational modifications such as phosphorylations, • RARs phosphorylation is altered in several breast cancer cells that are resistant to the antiproliferative effect of re- work on nuclear retinoic acid receptors which turned out to be crucial for their transcriptional ac- Bruck N, Vitoux D, Ferry C, Duong V, Bauer A, de Thé tinoic acid. n (RARs). tivity. H, Rochette-Egly C. A coordinated phosphorylation Since 1992 she is an INSERM Research cascade initiated by p38MAPK/MSK1 directs RARal- Our goal is to dissect the mechanisms and consequences of pha to target promoters. Director and in 1994 she moved to the RARs phosphorylation. We analyze how phosphorylation EMBO J. 28(1):34-47. (2009). IGBMC and became the leader of her own controls the dynamics of RAR-target genes’ transcription. Bour G, Lalevée S, Rochette-Egly C. Protein kinases team on RARs phosphorylation. She showed We also focus on how phosphorylation interferes with ubi- and the proteasome join in the combinatorial control that retinoic acid receptors are targets for of transcription by nuclear retinoic acid receptors. 1- Nuclear localization of RARalpha phosphorylation cascades which turned out quitination for RARs transcriptional activity and degrada- Trends Cell Biol. 17(6):302-9. (2007). (green) in breast cancer cells. tion. Given that many tumoral processes are characterized 2- to be crucial for their activity. n Gaillard E, Bruck N, Brelivet Y, Bour G, Lalevée S, Aberrant cytosolic localization of by aberrant kinase signaling pathways, we are engaged in a Bauer A, Poch O, Moras D, Rochette-Egly C. Phos- RARalpha (green) in stromal fibroblasts phorylation by PKA potentiates retinoic acid receptor from invasive breast carcinoma. large analysis of RARs phosphorylation in cancer cell lines alpha activity by means of increasing interaction with and tumor samples in correlation with their sensitivity to and phosphorylation by cyclin H/cdk7. retinoic acid. Proc Natl Acad Sci U S A.103(25):9548-53. (2006). The final important focus of our studies is to define how phosphorylation controls the activity of RARs during cell differentiation and embryonic development.< 2 53 Protein networks and complexes regulating eukaryotic mRNA decay RNA decay remains a complex and poorly understood process involved both in the constant renewal of mRNA used for protein synthesis and in the elimination of defective transcripts. Enzymes involved in this process act in general turnover and RNA quality control pathways. We will now highlights concentrate on the mechanism leading to activation of these factors. Using mechanistic, cellular and integrated approaches, • A new cellular compartment: We have identified several lines of research will be pursued using both yeast and characterized new cytoplasmic structures and mammalian cells as model systems: (i) How do cells involved in mRNA decay that contain, among distinguish aberrant from functional RNAs? (ii) How is others, decapping enzymes. mRNA decay regulated? (iii) Can we decipher the dynamic

shaping the future the shaping protein interaction networks underlying RNA decay? (iv) • Hidden transcripts: We have identified a new How is RNA decay integrated at the cellular level (e.g., with poly(A) polymerase and have shown that it is transcription and translation)? < involved in a RNA quality control pathway that targets a new type of transcript: Cryptic Uns- table Transcripts (CUTs). Bertrand Seraphin 1 • Protein complexes mediating RNA decay: Using a combination of approaches including innova- And RNA disappears probing complexity tive protein purification and mass spectrometry After studying at the ENS, Bertrand Seraphin strategies, we have contributed to the characte- obtained his PhD in 1988 at Curie Institute The control of gene expression allows cells and organisms rization of the organization, structure, function in Orsay on mitochondrial intron splicing, to adapt to changing conditions and to drive internal Pro- and activities of various protein complexes in- particularly on the role of a protein from grammes such as cell cycle or development. Gene expression volved in eukaryotic mRNA decay such as the a new family, the DEAD Boxes. From 1987 is an intricate multistep pathway in eukaryotes, allowing for to 1989, while he was a post-doctorate at multiple layers of regulations, but this process is also error exosome and the Exon Junction Complex (EJC) core. Brandeis University in Boston, USA with prone. Thus, potentially deleterious aberrant transcripts need Professor Rosbash, he studied yeast nuclear to be rapidly eliminated. • Regulating gene expression at a post-transcriptional level: splicing and brought to light new splicing Our goal is to understand how the RNA decay process We have characterized yeast and human deadenylases and complexes (commitment complexes). In some of their regulators to understand how this process contributes both to regulated gene expression and to the eli- 1991, he joined the EMBL, with Iain Mattaj is integrated in the cell and contributes to the control of mination of defective transcripts. Several pathways implica- and then became a team leader. His work on protein production. n ted in the degradation of eukaryotic RNAs have been identi- Lebreton A, Tomecki R, Dziembowski A, Séraphin characterization of splicing complexes (Sm fied. If several or most of the enzymes involved in this process B. Endonucleolytic RNA cleavage by a eukaryotic proteins, snRNP U1 et U6, etc.) brought him exosome. Nature. 456:993-996. (2008). are now known, the mechanisms activating specific enzymes to develop a protein complexes purification in defined conditions remain to be elucidated. For example, Mauxion F, Faux C, Séraphin B. The BTG2 protein is a strategy, the “Tandem Affinity Purification” general activator of mRNA deadenylation. we would like to decipher the mechanisms allowing cells to EMBO J. 27:1039-1048. (2008). (TAP method). In 2000, he integrated the discriminate bona fide mRNA from defective transcripts or 1- mRNA decay bodies (Dcp bodies CGM (Gif-sur-Yvette) where he studied RNA Dziembowski A, Lorentzen E, Conti E, Séraphin B. or P bodies) in HEK293 cells: red how the stability of specific RNA is regulated. This requires A single subunit, Dis3, is essentially responsible for decay, discovering new enzymes, a new cel- immunodetection of hDcp1a; blue: yeast exosome core activity. lular compartment and new nonannotated the characterization of the various protein complexes impli- Nat Struct Mol Biol. 14:15-22. (2007). DNA/nuclei. cated in RNA decay and of their dynamic interactions. Addi- 2- Monitoring the effect of mRNA transcripts: CUTs (Cryptic Unstable Trans- tional complexity arises from the connection of mRNA de- Wyers F, Rougemaille M, Badis G, Rousselle JC, decay factors on translation termina- cripts). His research has been continuing at Dufour ME, Boulay J, Régnault B, Devaux F, Namane tion: different yeast mutants harboring cay to other cellular processes. Integrated approaches are thus A, Séraphin B, Libri D, Jacquier A. Cryptic pol II the IGBMC since 2009. n transcripts are degraded by a nuclear quality control a reporter for stop codon readthrough necessary to decipher globally the contribution of mRNA pathway involving a new poly(A) polymerase. turn from white to red (right), or grow decay to gene expression control.< Cell. 121:725-737. (2005). better (left), on appropriate media. 2

55 Cell Biology

We are interested in the role of chromatin structure and of genome integrity nuclear architecture in the repair of Double Strand Breaks and the formation of chromosomal translocations. Our current objectives are: ● to visualize the dynamics of DNA damage response and highlights the formation of chromosomal translocations in living cells. ● to study the role of chromatin structure and nuclear architecture in DNA damage response and formation of • 3D tracking of the motion of DSBs in living chromosomal translocations. cells has shown that free chromosome ends have ● to identify novel chromatin related proteins that are limited motion and they are unable to roam the involved in DNA repair. cell nucleus.

future the shaping The insights gained from these in vivo studies will have • The repair protein Ku80 is involved in kee- a significant impact on our understanding of how the ping the free chromosome ends aligned. organization of repair in the context of a highly compacted • Analysis of translocation partners of unre- chromatin and compartmentalized nucleus contributes to paired chromosome breaks has shown that prevention of genomic instability. < they preferentially undergo translocations with Evi Soutoglou neighboring chromosomes. Nuclear architecture 1 • DNA repair factors are spreading around and chromatin structure the DSBs and they form microscopically visible in DNA repair structures known as repair foci. Mimicking of probing complexity repair foci by immobilization of a single repair Evi Soutoglou obtained her PhD at Each cell in the human body receives thousands of DNA factor to chromatin has shed light into their cri- the Institute of Molecular Biology and lesions per day. DNA lesions can interfere with genome re- tical role in the activation and the amplification Biotechnology (IMBB) in Crete, (Greece) on plication and transcription, and if they are not repaired or of the DNA damage response. transcription regulation in 2002. She then are repaired incorrectly, they lead to mutations that may • siRNA screen in mammalian cells revealed several chro- spent a short post-doc with Laszlo Tora’s threaten cell viability. The most deleterious DNA breaks are matin related proteins that are involved in DNA damage group at the IGBMC. In 2003, she joined the the Double Strand Breaks (DSBs) because unfaithful repair response and DNA repair (unpublished). n National Institute of Health (NIH) and worked can lead to the formation of cancerous chromosomal translo- with Tom Misteli on nuclear architecture cations. It is poorly understood why translocations between and chromatin dynamics in DNA repair. Evi chromosomes recur at specific break points in the genome created a system to visualize DNA double strand breaks in living cells. In 2009, she and even less is known about how ends from different DSBs DNA repair: easy to visualize, difficult to elucidate. returned to the IGBMC to set up her own meet in the cell nucleus. It was recently shown that broken Nagy Z, Soutoglou E. Trends Cell Biol. 19(11):617-29. (2009). team. n chromosome ends are positionally stable and unable to roam the cell nucleus and that unrepaired DSBs preferentially un- The emerging role of nuclear architecture in DNA repair and genome maintenance. Misteli T, Soutoglou E. dergo translocations with neighboring chromosomes. In our Nat Rev Mol Cell Biol. 10(4):243-54. (2009). group we are using a unique cell system to induce DSB at a 1- Chromatin decondensation induced specific chromosomal location and to follow the fate of da- Activation of the cellular DNA damage response in by tethering of the repair factor MDC1 the absence of DNA lesions. Soutoglou E, Misteli T. maged DNA in living cells in real time. Our goal is to inves- Science. 320(5882):1507-10. (2008). shown in 3D. tigate the dynamics of DSBs in relation to the surrounding 2- Dual color FISH with chromosome Positional stability of single double-strand breaks in 3 (green) and chromosome 19 (red) chromatin structure and nuclear architecture and to test how mammalian cells. Soutoglou E, Dorn JF, Sengupta K, paint probes in NIH 3T3 cells. this is related to their repair and their involvement in the Jasin M, Nussenzweig A, Ried T, Danuser G, Misteli T. Nat Cell Biol. 9(6):675-82. (2007). < formation of chromosomal translocations. 2

57 Chromatin modifications and regulation of

gene expression during differentiation We characterize the activities of several mammalian transcription factor complexes to get more insights in their function during cell growth and differentiation. The combination of different multidisciplinary approaches (i.e. ChIP-seq, proteomic, cell biology, imaging, and highlights bioinformatics) will lead to the identification of genes and pathways regulated by these complexes and their function • We identified and characterized several novel in mammalian cell differentiation and development. subunits of the human and Drosophila general trans- Our studies will also help to find ways to interfere with cription factor, TFIID. We described that different the action of these transcription factors, when needed TFIID complexes exist in the cells and that these in pathological situations. We anticipate that the results complexes regulate transcription differentially. of our research will have a major impact on the field and

shaping the future the shaping will potentially lead to a paradigm for contemporary • We discovered and characterized novel TATA metazoan transcription regulation and multiprotein complex binding protein (TBP)-like factors, such as TLF (also research.< called TRF2) and TBP2 (also called TRF3) and our work suggested that that these factors play a role as LÁszlÓ Tora cell-type specific initiation factors. • We demonstrated a tight coupling between ini- Studying transcription tiation of transcription and the 3’ maturation of pre- 1 factors and coactivators mRNAs. After graduating from the Eötvös Lorànd probing complexity • We discovered and characterized a new human University in Budapest with a PhD in histone acetyl transferase-containing coactivator Biochemistry and Molecular Biology in 1985, Our main research interest is to study how specific protein Laszlo Tora did his post-doc in Strasbourg to coding genes are turned on and off in the nucleus of a given study nuclear receptors, first with M. Bellard cell, during growth, differentiation and development. We use complex (called TFTC or SAGA) playing a role in chro- and then with Pierre Chambon. Between 1988 biochemical, genetic, cell biology, imaging and structural ap- matin remodelling. Motivated to explore the importance and 1989, he participated in the discovery that proaches to study the problem of control of gene expression of this factor in diseases, our estrogen and progesterone nuclear receptors findings have helped to unco- in different metazoan organisms. The lab’s research is broadly have two distinct activation domains. Since centred on three different axes, which all aim to better un- ver the mechanisms by which a polyglutamine expansion in 1993, he has led his own team at the IGBMC derstand RNA polymerase II transcription: (i) the role of dif- and has worked on transcription regulation Zhao Y., Lang G., Ito S., Bonnet J., Metzger E., Sawat- a subunit of SAGA leads to ferent proteins belonging in the TATA box binding protein subashi S., Suzuki E., Le Guezennec X., Stunnenberg photoreceptor dysfunction in mechanisms. In 1994, his team identified (TBPs) protein family, (ii) the role of TBP-associated factor H.G., Aleksey Krasnov, Sofia G. Georgieva, Schüle R., n and characterized three subunits of the TFIID Takeyama K.-I., Kato S, Tora L.* and Devys D.* A TFTC/ a mouse model of SCA7. (TAF)-containing complexes (i.e. TFIID and SAGA); and STAGA module mediates histone H2B deubiquitination, transcription factor and showed that different (iii) the role of histone acetyl transferase (HAT)-containing nuclear receptor activation and counteracts heterochro- TFIID complexes have a different regulation matin silencing. Molecular Cell. 29:92-101. (2008). chromatin remodelling coactivator complexes (i.e. SAGA 1- Detection of specific subunits of a histone activity. In 1997, Laszlo demonstrated the Kurshakova M.M., Krasnov A.N., Kopytova D., acetyltransferase complex (ATAC) by and ATAC) in gene regulation. Our current and planned ac- Shidlovskii Y.V., Nikolenko J.V., Nabirochkina E.N., coupling between transcription initiation and immuno fluorescence in mouse cells by using tivities aim to better understand gene regulatory processes in Spehner D., Schultz P., Tora L.* and Georgieva S.G.* polyadenylation. He then found TFTC and SAGA and a novel Drosophila export complex anchor antibodies against Ada2a (red) and Ada3 different cellular systems and also during the development of efficient transcription an mRNA export to NPC. (green). Merged images together with DNA proved its role in chromatin remodeling in intact vertebrate organisms. Our work on the different trans- EMBO J. 26:4956-4965. (2007). (blue) are shown in the left panels. 1998. In 2000 and 2004, he discovered and 2- Heat map representing density matrix after cription factors also contributes to a better understanding of Helmlinger D., Hardy S., Abou-Sleymane G., Eberlin characterized new TBP-like factors. n A., Bowman A., Gansmüller A., Picaud S., Zoghbi k-means clustering of genome wide transcrip- how a polyglutamine expansion in a SAGA subunit causes a H.Y., Trottier Y., Tora L.* and Devys D.* Glutamine- tion factor binding sites. Binding densities of neurodegenerative disorder (i.e. Spinocerebellar ataxia type Expanded Ataxin-7 Alters TFTC/STAGA Recruitment four histone acetyl transferases (PCAF, CBP, and Chromatin Structure Leading to Photoreceptor 7) or how the deregulation of the deubiquitination function MOF and TIP60) were clustered according Dysfunction. Plos Biology. 4(3):0432-0445. (2006). to p300 binding loci. of human SAGA causes metastatic cancers.< 2

59 Molecular and cellular

biology of cancer We aim to: ● complete the characterization of XRP44X in pre-clinical cancer models of metastasis and characterize the novel signaling pathway that is affected.

highlights ● use the hits from the screen of the world diversity set of compounds to develop compounds that will be useful to explore TTLL12 functions and establish whether they are • From functional characterization, thera- effective for tumour therapy. peutic target validation and high throughput screening, we have identified a compound, XR- ● study the functions of the genes in the gene-expression P44X, which inhibits the Ras oncogene – Net signature of future metastasis and use them to develop transcription factor signalling pathway (Wasylyk new treatments (Ano1). shaping the future the shaping et al., 2008) and metastasis in pre-clinical cancer models (patent application). ● validate our model for intimate crosstalk between HIF1alpha and Net, and use this knowledge to develop • We have characterized a novel gene, TTLL12, treatments for hypoxia related diseases.< whose expression increases with prostate cancer Bohdan Wasylyk progression (Wasylyk et al., 2010), validated it as a target for HTS (patent application), deve- 1 loped an assay, and identified hits in a screen of Biology applied to cancer a worldwide diversity set of compounds. After obtaining a PhD in Biochemistry at Glasgow University on DNA structure and probing complexity • Gene expression signatures have been identi- DNA interactions with RNA polymerase during fied that distinguish subgroups of HNSCC asso- Our mission is to create knowledge that could be beneficial transcription, Bohdan Wasylyk was awarded ciated with poor and good prognosis (Rickman for the treatment of cancer in the near future. We are inte- et al., 2008 and Jung et al., 2010, respectively). an EMBO Fellowship to join Pierre Chambon’s rested in studying the cancer-related functions of novel genes laboratory in Strasbourg in 1975. He worked on that we have identified, as well as known oncogenes and tu- • We have postulated a model for intimate crosstalk eukaryotic RNA polymerases and regulation between signaling pathways involving the master regulator mour suppressors. This involves studying their mechanisms of transcription by nucleosomes and promoter of the hypoxic response, HIF1alpha, and the transcription elements (TATA sequences and enhancers). of action, validating them as targets for high throughput factor Net (Gross et al., 2008; Serchov et al., 2010). n n screens (HTS), and establishing their usefulness as markers Bohdan was appointed CNRS Research for diagnosis and prognosis. Associate and focused his work on the We are studying several types of human cancer, including regulation of gene expression by oncogenes Wasylyk C, Zambrano A, Zhao C, Brants J, Abecassis (Ras, MDM2, etc.) and tumour suppressors head and neck squamous cell carcinoma (HNSCC) and J, Schalken JA, Rogatsch H, Schaefer G, Pycha A, 1 + 2 - Colocalisation of TTLL12 prostate cancer (CaP). HNSCC is particularly frequent in Klocker H, Wasylyk B. Tubulin tyrosine ligase like 12, with filaments. TTLL12 (red, 1 & 2) (p53). He has focused on particular cancers, link to prostate cancer through tubulin post-translatio- colocalises with vimentin (green, 1) including head and neck squamous cell France; it accounts for 12% of deaths by cancer in males, nal modification and chromosome ploidy. Int J Cancer. (2010). and microtubules (not shown), which carcinoma and prostate cancer. Bohdan and 5-year survival is about 30%. Prostate cancer is now the may to related to its effects on tubulin participated in HTS’s for small molecule most frequent cancer in men (350,000, 20% in Europe). Jung A, Briolat J, Millon R, de Reyniès A, Rickman modification, mitotic duration, D, Thomas E, Abecassis J, Clavel C and Wasylyk B. therapeutics that target p53, Ras and TTLL12. Treatment of primary tumours leads to initial remission that chromosome number instability and Biological and clinical relevance of transcriptionnally cancer. This has resulted notably in the identification later progress to invasive growth and metastasis. The reasons active human papillomavirus (HPV) infection in oropharynx squamous cell carcinoma. of XRP44X. n for relapse are not known and are the topic of many ongoing Int J Cancer. 126(8):1882-94. (2010). research projects. There is an urgent need to understand the biological mechanisms of cancer progression, in order to Wasylyk C, Zheng H, Multon MC, Debussche L and Wasylyk B. Inhibition of the Ras-Net (Elk-3) pathway develop new therapies and markers that could be used to and tumour growth in vivo by a novel pyrazole. 2 successfully treat cancer patients.< Cancer Res. 68(5):1275-83. (2008).

61 How the architecture of biological systems sheds light on their function

" We aim at determining biomolecular structures at the atomic level to position these molecules in functional complexes and to analyze or predict their motion. " P. Schultz

Our Programme aims at understanding the diffraction and diffusion, NMR, cryo elec- mechanisms of cellular processes by cor- tron microscopy and more recently, imaging relating the structural and the functional are associated with multi parametric data properties of their macromolecular compo- analysis and modeling approaches developed nents. The regulation of gene expression in in the bio-computing teams. Recombinant a broad sense, ranging from transcription and endogenous biological sample produc- regulation, chromatin structure, DNA to- tion, purification and biophysical charac- pology to messenger RNA translation, forms terization are key players in the core scientific activity of our community. the structure determination These fundamental biological processes are pipeline supported and de- 8 Groups of major importance for public health and veloped in our Programme. 29 Staff scientists the research conducted. These impact on our understanding of human diseases, drug The vision of structural bio- 24 Postdoctoral fellows target identification and drug optimization, logy for the next years will 21 PhD students for example, the studies on nuclear hormone pave the way towards inte- receptors and their co-regulators have strong grated cellular structural bio- 25 Engineers/Technicians implications for cancer, osteoporosis, obesity logy with the aim of addres- 1 Assistant and type II diabetes. sing multifactorial effects in the personalized context of a The research teams are highly interconnected unique human being. Our contribution to since multiple experimental approaches have this evolution translates as the multi-resolu- to be combined to address challenging pro- tion analysis of large complexes from their jects. Highly specialized structure determi- atomic structure to their in-cell distribution nation methods such as X-ray and neutron and interactome, in the investigation of the dynamics of biological processes at all levels INTEGRATED of complexity and in hybrid data integration • The structures of eukaryotic transcription factors and for knowledge production. In line with this co activators illuminate the mechanisms of transcriptional regulation and explain the action of hormones. commitment, the future Center of Integra- STRUCTURAL BIOLOGY ted Biology will host one of the two French • The ribosome machinery, determined in different functional states, explains the translation regulation nodes of INSTRUCT, the European infras- pathways and the inhibition strategies of antibiotics. tructure for integrative structural biology. n • Chromatin and DNA modifying enzymes are drug targets for human diseases. Our studies contribute to the better understanding of drug action and guide rational drug design. • Integrative bioinformatics and genomics combine evolutionary, ontologic and omics data to extract knowledge. • We are committed to the development of new concep- tual methodologies and novel modes of instrumentation to lead us towards tomorrow’s discoveries. 63 Structural biology

of epigenetic targets Most epigenetic players involved in the regulation of gene expression are multi-protein complexes. We are addressing the challenge of characterizing in molecular terms the biologically relevant complexes (that contain our targets) by developing a structural biology-based approach, integrating highlights identification, production, purification, biophysical characterization and structure determination. Combining multi-resolution structural analysis with biologi- • PRMTs: Co-activator-associated arginine cal-functional studies will allow us to gain a better unders- methyltransferase 1 (CARM1 also known as tanding on how these complexes function in a biological PRMT4) methylates a large variety of proteins which are vital to gene expression. context. A structure-based approach will also be used to Our high resolution structures of several isolated discover, generate and validate novel epigenetic regulators, modules of CARM1 have highlighted molecu- future the shaping since the availability of such compounds is at the heart of lar switches that expand our understanding of new therapies against the expanding number of diseases how CARM1 regulates its biological activities. shown to depend on epigenetic mechanisms. < Furthermore, complementary functional studies have provided clues on the mode of binding of Jean Cavarelli arginine-containing substrate or product peptides to CARM1. 1 Understanding biology at • Histone chaperones: The structure of the C-ter- the atomic scale probing complexity minal part of Spt6 revealed a non-canonical tan- Educated in chemistry, Jean Cavarelli chan- dem SH2 domain essential for Spt6 interaction ged his focus to biology and obtained a PhD Chromatin structure is a major barrier to all nuclear with the hyperphosphorylated RNA Polymerase in Structural Biophysics at the University of processes and its modulation is essential for correct cell II CTD. Furthermore, structural characteriza- Strasbourg with Dino Moras’s team, focu- tion of the interaction between Spt6 and Iws1 growth. There is now clear evidence that defects in chro- sing on crystallographic studies of protein- matin modulation are responsible for a wide range of di- leads to specific mutants affecting yeast viability and we nucleic acid complexes (1987). He spent two seases, including cancer. Epigenetic modifications have are deciphering the role of each partner in vivo. years as a post-doctoral fellow at Purdue a large impact on chromatin structure, acting in synergy University in West-Lafayette, Indiana, USA with ATP-dependent remodelers, histone variants and his- • Technological developments: Besides our scientific com- where he solved the structure of an insect mitments, our development of multi-expression tools and tone chaperones to regulate nuclear mechanisms. By com- virus in 1989. Beginning as Associate Pro- our structural and crystallographic expertise is essential to bining state-of-the-art biochemical and crystallographic tackle our internal and collaborative projects. n fessor and then Full Professor in 1996 at the techniques, we aim to understand chromatin remodeling Bieniossek, C., Nie, Y., Frey, D., Olieric, N., Schaffitzel, University of Strasbourg, he worked for a C., Collinson, I., Romier, C., Berger, P., Richmond, T.J., at the molecular level. Three main targets are the current Steinmetz, M.O., Berger I. Automated unrestricted long time on aminoacyl-tRNA synthetase- focus of our research: protein arginine methyltransferases multigene recombineering for multiprotein complex complexes before focusing on epigenetics production. Nat. Methods. 6:447-450. (2009). (PRMTs), histone chaperones and histone deacetylases targets, notably PRMTs. He has participated (HDACs). Furthermore, we are also developing structure- Troffer-Charlier N., Cura V., Hassenboehler P. , Moras in several collaborative projects on proteins D. and Cavarelli, J., Functional insights from structures based rational approaches to characterize small molecule of coactivator-associated arginine methyltransferase 1 related to human diseases, nuclear receptor 1- Structure of the PRMT catalytic domains. EMBO J. 26(20):4391-4401. (2007). coactivators and transcription factors. The modulators of the biological activities of our targets since domain of CARM1with bound SAH at they are frequently involved in human diseases. Romier, C., James, N., Birck, C., Cavarelli, J., Vivarès, 2.2 Å. Two monomers are shown here research of his team is currently focused C., Collart, M.A., Moras, D. Crystal structure, bioche- Our team also participates in collaborative research on se- (residues 140-480 of mouse CARM1) on epigenetic targets. He is also strongly mical and genetic characterization of yeast and E. building an active dimer. cuniculi TAFII5 N-terminal domain: implications for involved in teaching, leading several Pro- veral related projects which require our specific expertise. 2- Model of the Spt6/Iws1 complex. TFIID assembly. J. Mol. Biol. 368:1292-1306. (2007). grammes in structural biology and structural Present collaborations concern the structural studies of bioinformatics at the University. n complexes of cancer-related targets such as the Translatio- Klein, F.A.C., Atkinson, R.A., Potier, N., Moras, D. and Cavarelli, J. Biochemical and NMR mapping of the nally Controlled Tumor Protein (TCTP) and the mRNA interface between CREB-binding protein and ligand of human histone H4.< binding domains of nuclear receptors: beyond the LXXLL motif, J. Biol. Chem. 280:5682-5692. (2005). 2 365 Biocomputing

Our goal will be to use computational tools to study structure-function relationships of macromolecular complexes implicated in transcription regulation, in collaboration with other IGBMC teams involved in structural biology, experimental biophysics and bioinformatics. highlights We will use atomic-level simulation studies of nuclear receptors to further our understanding of the molecular mechanisms of ligand recognition and allosteric communication in these proteins. Specifically, we shall study the role of phosphorylation-mediated structural and dynamical • Identification of dynamically coupled amino changes, the associated molecular mechanisms and impli- acids in the I-domain of the integrin LFA-1 cations for allosteric communication. uncovers an allosteric network that participates future the shaping We will also work towards the modeling of large macromo- in the complex signal transduction mechanism lecular assemblies using hybrid computational and experi- of integrins. The calculations show that active mental methods. < compounds can interfere with this dynamically coupled network and result in the perturbation Annick Dejaegere of signal transmission. Computation for biology 1 • A dynamically coupled amino acid network Annick Dejaegere obtained a PhD in Physical is identified in the ligand-binding domain of Chemistry at the Free University of Brussels human peroxisome proliferator-activated recep- in Belgium. In 1989, she studied interactions probing complexity g tor- nuclear receptor protein. This network was in aromatic molecules with Jacques Reisse. Molecular interactions that occur between biological mo- shown to be influenced by the presence of ago- She joined Martin Karplus’ team for her lecules and their ligands are underlying the vast array of nist molecules. post-doc at Harvard University, USA. She processes that take place in a living organism are. We are worked on the reactivity of phosphates and trying to understand and characterize the molecular re- • Free energy decomposition of protein-protein and pro- proposed an original interpretation on the cognition processes using computational approaches that tein-ligand complexes provides insight into the molecular role of solvation in the reactivity of these permit the characterization of the molecule-level dynamics mechanisms of supramolecular assembly and pinpoints hi- molecules. ghlights interactions that can be used as starting points for and aim to understand the thermodynamics of molecu- In 1993, she joined the NMR group of Jean- drug design. n lar recognition processes and to further comprehend the François Lefèvre at the (Louis-Pasteur) Uni- structural and dynamic consequences of such interactions. versity of Strasbourg, and developed pre- For example, we are trying to elucidate how molecular G. Moroy, A. Dejaegere, R.H. Stote, “Molecular basis dictive models of chemical shift for NMR signals are transmitted in biomolecular systems. Recent for BH3 domain recognition in the BCL-2 protein family: Identification of conserved hot-spot interac- structure determination. In 1995, her work applications focus on the nuclear receptor superfamily of tions”. J. Biol. Chem. 284:17499-17511. (2009). highlighted original links between DNA ligand-activated transcription factors which play a primor- C. Browning, E. Martin, C. Loch, JM Wurtz, D. Mo- backbone structure and chemical shift. dial role in complex processes such as cell differentiation, ras, R.H. Stote, A.P. Dejaegere, I.M.L. Billas, “Critical In 2002, she joined IGBMC where she leads Role of Desolvation in the binding of 20-Hydroxyec- development, and homeostasis. We study the interplay a team dedicated to the computational study dysone to the ecdysone receptor”. 1- Representation of functional motions J. Biol. Chem. 282:32924-32934. (2007). of protein complexes. n between ligand binding, structural changes and allostery in the I-domain of the integrin LFA-1. in these receptors. Other proteins under study include T. Gaillard, E. Martin, E. San Sebastian, F. P. Cossio, 2- Representation of the dimer of the the integrin cell adhesion proteins. These projects are de- X. Lopez, A. Dejaegere, R. H. Stote, “Comparative ligand binding domains of the nuclear Normal Mode Analysis of LFA-1 Integrin I-domains” receptors RAR and RXR. Analysis of the veloped in collaboration with experimental groups at the J. Mol. Biol. 374:231-249. (2007). stabilizing amino acids at the dimer inter- IGBMC and elsewhere. These studies also provide impor- V. Lafont, M. Schaefer, R. H. Stote, D. Altschuh, A. face shows a conserved motif (highlighted tant information that can be exploited in rational drug Dejaegere « Protein-protein recognition and interac- in surface representation). tion hot spots in an antigen-antibody complex: free design projects that are developed at the interface of mole- energy decomposition identifies “efficient amino cular biology, biophysics and organic synthesis groups.< acids”. » Proteins. 67:418-434. (2007). 2 367 Biomolecular

Nuclear Magnetic Resonance The availability of a new 700 MHz spectrometer equipped with a high sensitivity probe opens new perspectives for the group. Efforts to describe disordered and functionally important regions of proteins will be continued. Particular emphasis will be put on the study of N-terminal regions of highlights several nuclear receptors, aiming at understanding the rules that govern their evolution. Efforts will also be devoted to study molecular interactions • We have elucidated the solution structure of within large complexes such as nucleosomes or within cel- several domains of transcription factor TFIIH lular environments.< and have studied their interaction properties. In particular, we have shown that the self-association properties of p8, are closely linked to trichothiodystrophy. future the shaping

• The solution structure of the C-terminal zinc finger domain of the oncoprotein E6 was elu- Bruno Kieffer cidated. The structure displays a novel fold and suggests a model of interaction with PDZ domains. Understanding the intimate 1 nature of proteins • Two homologous zinc finger domains of the Bruno Kieffer obtained his PhD on the NMR Deubiquitination complex of SAGA were stu- of proteins with Jean-François Lefèvre’s team died. Despite a common zinc binding motif, the at Strasbourg University in 1992 and reloca- probing complexity two domains exhibited distinct secondary struc- ted to Oxford University for postdoctoral re- NMR spectroscopy provides invaluable insights into the tures and functional properties. In particular, it was found that the SCA7 zinc finger of ATXN7 search where he resolved the first structure of structural and dynamical features of biomolecular sys- the surface protein CD59 whilst in the group tems. We are taking advantage of NMR, combined with protein was able to bind nucleosomes with high affinity. of Iain Campbell. other structural biology methods, to investigate molecular On his return Bruno was appointed Associate • The concept of fractal dimension has been suggested as a properties that are important to achieve a given biological Professor at the ESBS in Strasbourg where functionally relevant property to describe disordered seg- function. Recent topics which have been addressed by the besides teaching bioinformatics and biophy- ments of proteins. n group include the study of several structural domains of sics, his research continued employing NMR transcription factors such as TFIIH and SAGA. to study bio-molecular behavior and function. The group is also involved in the study of the Human Augé S, Schmit PO, Crutchfield CA, Islam MT, Harris In collaboration with the other teams of the Papilloma Virus E6 protein and its interaction with host DJ, Durand E, Clemancey M, Quoineaud AA, Lance- Institute and the IGBMC, Bruno worked on lin JM, Prigent Y, Taulelle F, Delsuc MA. NMR mea- PDZ domains. Often, the molecular plasticity of proteins sure of translational diffusion and fractal dimension. transcription factors such as TFIIH and SAGA is crucial for their function, as illustrated by the self-asso- Application to molecular mass measurement. and successfully determined the solution J Phys Chem B. 113:1914-1918. (2009). ciation properties of p8, the smallest subunit of TFIIH or structure of the PH domain of the TFIIH p62 Vitorino M., Coin F., Zlobinskaya O., Atkinson A.R., sub-unit, and three years later, the 10th sub- by the role of flanking regions of PDZ domains in pro- Moras D., Egly J.-M., Poterszman A., Kieffer B. Solu- 1- Structure of the TFIIH MAT1 tein-peptide interactions. Recently, novel experimental tion structure and self-association properties of the RING domain illustrating the dialog unit, called p8. p8 TFIIH subunit responsible for trichothiodystrophy. between structure and sequence Continuing his close professional relationship and theoretical tools have been developed to study the J Mol Biol. 368(2):473-480. (2007). 2- Structure of the TFIIH p8 subu- disordered states of proteins that are involved in signaling with the ESBS, Bruno elucidated the structure Nominé Y., Masson M., Charbonnier S., Zanier K., nit and the corresponding 1H-15N of the human papillomavirus E6 oncoprotein. mechanisms. These tools are currently used to study AB Ristriani T., Deryckère F., Weiss E., Orfanoudakis G., HSQC spectrum This research led to a registered drug patent domains of nuclear receptors such as RARg and to des- Kieffer B., Travé G. Structural and functional analysis of papillomavirus E6 oncoprotein: New insights in for medical protein control. n cribe their modification upon phosphorylation.< the molecular pathways of HPV-mediated pathogenesis. Molecular Cell. 21(5):665-678. (2006).

2 369 Large complexes

involved in gene expression In the coming years we will focus on understanding the function of large macromolecular complexes involved in transcription and translation. Our particular aim is to determine the functional and structural determinants of ligand-dependent transcription activation of nuclear receptor highlights and co-regulators and to address the mechanism of action of chromatin associated complexes. We will also explore the specific differences between the pro- and eukaryotic In the past few years we have made major progress protein synthesis machineries. For this, we will pursue in the study of bacterial translation initiation com- an integrative structural biology approach, combining, plexes and human nuclear receptor complexes: biochemistry, bio-physics and bio-informatics, with software • We have trapped a 70S ribosome initiation com- developments for three-dimensional reconstruction and plex with initiation factor IF2 and revealed the future the shaping multi-state image processing as well as an enhanced conformational changes of IF2 and of the ribo- integration of multi-scale tools. < some occurring upon GTP-hydrolysis. Bruno Klaholz • We have also visualized for the first time the 30S initiation complex in the presence of the initiator Integrative biology to tRNA and initiation factors IF1 and IF2, revealing understand the mechanisms 1 the cooperative stabilization of the tRNA in this of gene expression first event of gene decoding during protein synthe- Early on, Bruno Klaholz became interested sis. probing complexity in molecular recognition. During his PhD he Transcription and translation are fundamental molecular • We have also achieved major advances in the worked with Dino Moras’ team at the IGBMC mechanisms of gene activity regulation with profound study of the architecture of a full nuclear receptor and became involved in crystallography to determine the three-dimensional structure of implications for human health. The ligand-dependent complex, while previously structural studies have nuclear receptors and to analyze their specific transcriptional regulation by nuclear receptors bound to been limited to the individual ligand-binding and DNA-bin- interactions with pharmaceutical ligands. In DNA response elements involves the transient assembly ding domains. 2001, he began his post-doc at Imperial Col- of large co-regulator complexes. These trigger chromatin lege, London and extended his knowledge remodeling and facilitate the assembly of the general trans- • Furthermore, we have shown the important role of mRNA to single particle cryo-electron microscopy, cription machinery on the promoter of the target gene. structure as illustrated by the transient ribosome-entrapment by a folded mRNA. Notably, sequence and structure analysis allowing him to visualize the 3D structure of Gene expression is also regulated at the level of protein A. G. Myasnikov, A. Simonetti, S. Marzi, B. P. Klaholz. suggests the existence of a conserved site on the ribosome for molecules in their native state. At that time he synthesis, for example, by protein factors that bind to the Structure-function insights into prokaryotic and eukaryotic translation initiation. binding regulatory mRNAs. n investigated the molecular function of ribo- ribosome during the translation initiation, elongation and Curr. Op. Struct. Biol. 9:300-309. (2009). somes during termination of protein synthe- termination phase. A. Simonetti, S. Marzi, A. G. Myasnikov, A. Fabbretti, sis. In 2003, he returned to the IGBMC and The initiation phase is strongly regulated by factors and G. Yusupova, M. Yusupov, C. O. Gualerzi, B. P. Klaholz. subsequently created his own research team also by the mRNA itself and well-characterized reaction Structure of the 30S translation initiation complex. Nature. 455:416-420. (2008). with a focus on the molecular mechanisms intermediates of the initiating ribosomal nano-machinery that regulate gene expression. For the study S. Marzi, A. G. Myasnikov, A. Serganov, C. Ehresmann, 1- Structure of the 30S translation are potential targets for antibiotics. Both transcription and P. Romby, M. Yusupov & B. P. Klaholz. Structured initiation complex. of these large complexes he favors an inte- translation complexes represent large, transient macromo- mRNAs regulate translation initiation by binding to the 2- The conserved site on the grated approach using electron microscopy, platform of the ribosome. Cell. 130:1019–1031. (2007). lecular assemblies that we investigate by using an integra- ribosome for binding regulatory crystallography, biochemistry and bioinfor- mRNAs during translation pre- tive structural biology approach with crystallography and A. G. Myasnikov, S. Marzi, A. Simonetti, A. M. Giuliodori, matics. Through advanced image processing C. O. Gualerzi, G. Yusupova, M. Yusupov, B. P. Klaholz. initiation cryo-electron microscopy forming the core.< Conformational transition of initiation factor 2 from the and statistical analysis he also developed GTP- to GDP-bound state visualized on the ribosome. approaches to separate different structural Nat. Struct. Mol. Biol. 12:1145-1149. (2005). states in a single sample. n

2 371 Expression

of genetic information Three aspects of transcription regulation by nuclear hormone receptors will be investigated: • The role of DNA in the correct positioning of the receptors and the architecture of their complexes with cofactors. • The molecular mechanisms that control the binding of highlights cofactor proteins. • The structural aspects of NHR action at the chromatin level. Integrative structural biology tools will be used and • The functional relevance of two mutually exclu- sive signature motifs of the ligand binding domain developed to characterize structural and functional aspects that partition the nuclear receptor superfamily both in vitro and in the cell. For the vitamin D and retinoids into two classes with specific molecular pathways receptors, the investigation will be extended to the tissue is illustrated by the allosteric control of retinoic and animal model (mouse) levels. <

acid receptor (RAR) activity by phosphorylation. future the shaping

• Role of the ligand and drug design: i) the work on the insect ortholog USP of RXR provides novel insights into receptor-ligand binding evolution Dino Moras and dynamics; ii) a structural water channel has 1 been characterized and used to design a more potent superagonist for the Vitamin D Receptor. Molecular mechanisms of gene expression • The structural basis for understanding the role of probing complexity DNA in the spatial organization of NHR hetero- DIno Moras graduated with a degree in Che- mistry, then went on to study structural bio- Our goal is to understand the molecular mechanisms that dimers in functional transcription complexes with cofactors has been investigated using a combina- logy as a post-doctorate fellow with Michael control gene expression in human cells and animal models. tion of solution techniques. Several structures have Rossmann at Purdue University, West Lafa- We are focusing on the study of transcriptional regulation been determined. yette, Indiana, USA. Notably, he participa- by nuclear hormone receptors (NHR), using integrative ted to the discovery of the Rossmann Fold structural biology approaches to decipher the structural • The first structure of HIV integrase in complex with DNA in 1974. Dino returned to France in 1975 and basis of the communication between nuclear receptors, and the cellular cofactor LEDGF/p75 was determined by created a team at the Institute of Chemistry DNA and components of the basal transcription machi- EM. in Strasbourg. In 1980, he founded the Crys- nery. NHR-mediated transcription is regulated by ligands tallography and Structural Biology Depart- • The X-ray structure of p8/Tfb5 in complex with another and post-translational modifications. Understanding the TFIIH subunit was elucidated, providing a molecular basis ment at the IBMC. In 1990, he discovered the role of these factors in molecular control mechanisms (ie. n partition of amino-acyl-tRNA synthetases in Michel F, Crucifix C, Granger F, Eiler S, Mouscadet JF, for trichothiodystrophy, a rare disease. allosteric regulation of the activity), has important impli- Korolev S, Agapkina J, Ziganshin R, Gottikh M, Na- two classes and determined the first three- cations for pharmacological applications (drug design). zabal A, Emiliani S, Benarous R, Moras D, Schultz P, dimensional structure of a class II tRNA- Ruff M. Structural basis for HIV-1 DNA integration in Today’s integrative structural biology demands multi- the human genome, role of the LEDGF/P75 cofactor. synthetase. Dino then worked on nuclear scale structural data and their translation into functional EMBO J. 28:980-91. (2009). receptors in collaboration with Pierre Cham-

knowledge. We use X-ray crystallography, EM and NMR Hourai S., Rodrigues L.C., Antony P., Reina-San- bon and elucidated the first crystal structure 1- RXR/RAR on the RARβ2 promotor Martin B., Ciesielski F., Magnier B.C., Schoonjans K., of the retinoic acid receptor. From 2007 to techniques to determine structure and dynamics at dif- Mourino A., Rochel, N., Moras D. Structure-based within a nucleosome.. ferent levels of detail, ranging from atomic resolution of design of a superagonist ligand for the vitamin D 2- The HIV-1 integrase in complex with 2009, he was Director of the IGBMC. n nuclear receptor. Chem. Biol. 15:383-392. (2008). individual proteins or small complexes to tomographic a cellular co-factor (LEDGF), viral and cellular DNA. analysis of large particles. Macromolecular complexes can Iwema T., Billas, I.M.L., Beck Y., Bonneton F., Nieren- garten H., Chaumot A., Richards G., Laudet V., Moras be relatively stable (e.g. ribosomes) or transient. For the D. Structural and functional characterization of a latter, the temporal component is crucial and reconstitu- novel type of ligand-independent RXR-USP receptor. EMBO J. 26:3770-3782. (2007) tion of the proper sequence of events in the cell using light < Yusupova G., Jenner L., Rees B., Moras D., Yusupov microscopy tools is an essential part of our studies. M. Structural Basis for messenger RNA movement on the ribosome. Nature. 444:391-394. (2006) 2 373 Evolutionary systems biology

Addressing the complexity of biological systems will involve automatic value-added data processing and analysis, requiring extensive computational power as well as rapid access to dispersed but synchronized data resources. In this context, our research will focus on the development highlights of original bioinformatics solutions deployed on advanced computer and data technologies to ensure automated, • AlExSys (Alignment Expert System) drives opti- updated and sustained analyses. mal strategies for high quality multiple alignment Our approach of comparison and modeling of biological and analysis of complete sequences by dissecting systems will take advantage of the postulate “what is im- the relationships between Programme strengths/ portant is generally conserved”: i.e., billions of years of evo- weaknesses and the information content of extensive lution and selection constitute a discriminating filter and a

set of sequences. future the shaping unique source of information for interpreting what the new • SM2PH-db involves automatically launched and data actually mean and how they can be used to address questions that need to be answered. < updated cascade of data processing and analyses em- Olivier Poch bedded in the BIRD system and Decrypthon data 1 and computer grid to allow the study and interpre- Toward integrative tation of the molecular consequences of mutations bioinformatics in the context of all known human monogenetic probing complexity diseases. Having been simultaneously at the Pasteur Institute and the IGBMC, Olivier Poch obtained Our research is focused on the management of the ubi- • The ortho-proteogenomics approach combines a PhD from Strasbourg University on the de- original sequence analysis tools with proteomics ap- quitous «data overload» from today’s high-throughput termination of rabies virus genes sequence in proaches highlighting the extensive sequence error technologies. We use complementary bottom-up and top- 1987. He then focused on the analysis of the rate in well studied proteomes and allowing the crea- down approaches to study the behaviour and evolution tion of Programme cascades for automatic predic- viral protein sequences and predicted that all of biological systems, such as “hyperstructures” (macro- tion of sequence-error and proteome-level curation. monomeric polymerases from all living orga- molecular complexes, organelles, viruses…) or biological nisms may share a common unifying fold. networks (metabolic, transcriptional, interaction as well • Following our study of the Bardet-Biedl Syndrome and the In 1992, he became interested in the experi- as developmental or disease-related networks…). In the characterization of the BBS10 and BBS12 genes, extensive mental study of the yeast cell cycle while he bottom-up approach, we study basic components and in- analysis and genetic diagnosis of hundreds of families still worked on bioinformatics analysis, no- tegrate the data to detect relevant patterns (e.g., proteins allowed the identification of 28 novel mutations. This study tably on tRNA synthetases where he contri- Bard N, Bolze R, Caron E, Desprez F, Heymann M, Frie- highlights the burden of private mutations in an extensively and their interactions within a complex). In the top-down drich A, Moulinierr L, Nguyen NH, Poch O Toursel T (2010) buted to the discovery of 2 classes in this an- Decrypthon Grid – Grid resources dedicated to neuro- heterogeneous disease and confirms that BBS1, BBS10 and cestral protein family. In 1997, he joined the approach, we establish our knowledge of the system and muscular disorders in “Studies in Health Technology and BBS12 are the most frequently mutated genes. n attempt to disassemble it, e.g. to study normal and abnor- Informatics», IOS Press, in press. (2010). IGBMC to create a Bioinformatics laboratory and develop original approaches for multiple mal (disease) processes. This involves the development of: Aniba MR, Poch O, Marchler-Bauer A, Thompson JD, - Original algorithms and software based on an evolutio- (2010) AlexSys: a knowledge-based expert system for sequence alignment and comparative geno- multiple sequence alignment construction and analysis mics programmes. He then focused on more nary approach to analyse hierarchical systems in the light Nucleic Acids Res. in press. (2010). integrative approaches working on functional of their conservation and distribution in eukarya, 1- Derivation of the mean square error in Friedrich A, Garnier N, Gagnière N, Nguyen H, Albou LP, the Multidimensional fitting algorithm genomics data, ontology development, clus- - New data system architectures suitable for computer and Biancalana V, Bettler E, Deléage G, Lecompte O, Muller 2- J, Moras D, Mandel JL, Toursel T, Moulinier L, Poch O. Pathways of PtdIns5P synthesis and tering algorithms and recently, turned toward data grids to allow rapid retrieval, organization and explo- transformation : a)Schematic representa- SM2PH-db: an interactive system for the integrated ana- data mining and knowledge extraction ap- ration of raw data and information and to extract hidden lysis of phenotypic consequences of missense mutations tion of phosphoinositides, fatty acids are re- in proteins involved in human genetic diseases. proaches. n knowledge, presented only for PtdIns with co-evolving Hum Mutat. 31(2):127-35. (2010). complexes highlighted. b) Phylogenetic - Bioinformatics pipelines for quality control, integration, Muller J, Stoetzel C, Vincent MC, Leitch CC, Etal...Poch O, distribution of proteins implicated in the analysis and real time maintenance of interconnected ge- Mandel JL, Dollfus H. Identification of 28 novel mutations PtdIns5P metabolism in 39 eukaryotic nomics data with the goal of understanding disease origins in the Bardet-Biedl syndrome genes: the burden of private organisms c) Inferred PtdIns5P metabolism mutations in an extensively heterogeneous disease. in different organisms. and identifying and developing new therapeutic targets.< Hum Genet. 127(5):583-93. (2010). 2 375 Architecture of nucleoprotein systems

by 3-D Electron Microscopy Future developments in the image analysis of large datasets of eukaryotic transcription complexes will reveal finer morphological details as well as a larger number of discrete conformational states. This wealth of information will allow us to fit more accurately atomic structure into our cryo EM highlights maps and to reveal the dynamic processes underling transcription initiation. The analysis of frozen hydrated cell sections aims at posi- • TFIID flexibility: We have characterized major tioning the transcription process in its cellular context and conformational changes of the transcriptional co- to visualize the molecular complexes in their functional activator TFIID and found that the presence of chromatin environment. More complex in vitro systems will the Taf2 subunit stabilizes an active conformation. be established and studied to determine the structures of

shaping the future the shaping integrated biological architectures taking into account trans- • Activation of transcription: The cryoEM struc- cription factors in their chromatin context. < ture of a complex containing TFIID, TFIIA and the Rap1 activator assembled on a ribosomal gene promoter revealed the role of TFIIA in the activa- Patrick Schultz tion process. TFIIA is part of a molecular switch that changes conformation upon interaction with Visualizing molecules to the activator and triggers initiation complex as- understand their function 1 sembly. Patrick Schultz graduated with a degree in Mo- lecular Biology and Genetics from Strasbourg • In vivo organization of transcription: The corre- probing complexity University and obtained his PhD in 1987 on the lation of histone modifications, chromatin com- Our team deciphers the three-dimensional organization of paction and active RNA polymerase positions organization of chromatin working in Pierre macromolecular complexes by using high resolution cryo- places the transcriptional scene within the cell Oudet’s team. During his postdoc at EMBL (Hei- Electron Microscopy (EM) to visualize single molecules in delberg), he had the opportunity to use cryo their native state and image analysis to extract signal from nucleus. We found that transcription occurs in decondensed Electron Microscopy which opened a new pros- noise. We study how basal transcription factors interact chromatin at a fixed distance from the heterochromatin in- pect for visualizing molecules in their native, with the promoter of protein-encoding genes and analyze terface. hydrated, environment. When he returned to the transmission of activation signals mediated by cis-ac- Strasbourg he focused on the structural studies ting transcription factors towards the basal transcription • Mechanism of viral DNA integration: In collaboration of multiprotein complexes involved in transcrip- with Marc Ruff we determined a 3-D model of the HIV-1 machinery in order to trigger increased transcription. tion and in its regulation. In 1991 he published Integrase in the presence of DNA molecules. The cryoEM The study of different intermediate states reveals snapshots the first 3-D model of a eukaryotic RNA polyme- Papai G, Tripathi MK, Ruhlmann C, Layer JH, Weil structures reveal the detailed molecular architecture of the rase. In 1994, the newly created IGBMC brought of dynamic processes that highlight the conformational PA and Schultz P. TFIIA and the transactivator Rap1 n integration complex. him closer to X-ray crystallography and NMR changes of these nanomachines during transcription ini- cooperate to commit TFIID for transcription initiation, Nature. 465(7300):956-60. (2010). and since then he has tried to integrate these tiation. These approaches were applied to several molecu- complementary structural approaches. Fol- lar systems including the SAGA and TFIID coactivators, Papai G, Tripathi MK, Ruhlmann C, Werten S, Crucifix C, Weil PA, Schultz P. Mapping the initiation binding 1- Three-dimensional model of the HIV lowing Pierre Chambon’s pioneering work on but also to other systems such as TFIIH, TFIIE, RNA Po- Taf2 subunit in the structure of hydrated yeast TFIID. Structure. 17(3):363-373. (2009). integrase (blue) complexed to the cellular transcription factors, he identified a structural lymerase I, DNA Topoisomerase II or HIV integrase, in co-factor LEDGF (grey) in interaction with the model for TFIIH in 2000 and worked on the com- collaboration mainly with IGBMC team leaders. Michel F, Crucifix C, Granger F, Mouscadet JF, viral DNA (modeled in two distinct conforma- Korolev S, Gottik M, Nazabal A, Emiliani S, Benarous prehension of the structure and the function of As part of an integrated vision of cellular structural bio- tions in gold) and the cellular DNA (red). R, Moras D, Schultz P and Ruff M. Mechanism for 2- Extended chromatin fiber (red) the TFIID complex. More recently, his research logy we analyze the organization of transcription within viral DNA integration in the human genome by the HIV-1 integrase and role of human LEDGF. EMBO J. visualized in an electron tomogram of a mouse has turned towards understanding chromatin the nuclei of rod photoreceptors. The biological system 28(7):980-991. (2009). rod photoreceptor nuclei. Dense heterochroma- structure and the transcription units organiza- tin is depicted in green whereas the euchromatin used is a mouse model of a human disease: the type 7 tion within the cellular environment. n Thauvin C, Rickling S, Schultz P, Célia H, Meunier S, domain appears in blue. Spinocerebellar Ataxia. Chromatin organization, histone Mioskowski C (2008) Carbon nanotubes as templates for polymerized lipid assemblies. modification and transcriptional activity were correlated Nat Nanotechnol. 3(12):743-8. (2008). in this context. < 2 377 Ribosomes

X-ray crystallography of the yeast ribosomes will allow us to investigate the mechanism of regulation of translation in eukaryotes. This study will create a basis for the beginning of x-ray study of translation system in human cells. highlights We will continue the investigation of the mechanism of translocation by x-ray structure determination of different • We have determined the first crystal struc- ribosome functional complexes from bacteria and yeast. ture of eukaryotic 80S ribosome from yeast. We have determined structures of several bacterial New antibiotics developed for inhibition of the ribosome 70S ribosome complexes containing tRNAs and activity in bacteria and fungi will be studied by x-ray crys- different mRNAs. We have proposed a mecha- tallography. <

nism of mRNA movement on the ribosome du- future the shaping ring translation.

• Our study of codon-anticodon interactions of tRNAPhe containing hypermodified nu- Marat Yusupov cleoside in the anticodon loop at position 37 All about the ribosome (ms2i6A37) have shown how natural modifi- 1 cation is involved in preventing frame-shifting In 1978, Marat Yusupov began his research and stabilizing mRNA-tRNA interactions. at the Institute for Protein Research in Pus- hchino, Russia. In 1986, he obtained his PhD • High resolution structures show that tRNA probing complexity on the study of ribosome structure. He then in the A and P sites communicate through The ribosome is a large ribo-nucleoprotein complex with a protein rich environment suggesting a supervised a research team at the Institute total molecular mass of 2 500 000 Dalton in bacteria and mechanism for the control of these tRNAs for Protein Research and collaborated with 3 300 000 Dalton in yeast. Several components contri- Dino Moras for ribosome x-ray study. position/function by the ribosome. bute to the greater weight and complexity of eukaryotic In 1996, he joined the University of Califor- nia in Santa Cruz, USA and continued his ribosomes: RNA expansion segments that are inserted into • We have identified the network of ribosomal elements work on the ribosome. In 2001, he made a the evolutionary conserved rRNA core and additional 25 involved in proofreading of tRNA by comparing three major discovery with Harry Noller, Jamie H. proteins. crystal structures of the 70S ribosome with an empty A site The ribosome performs protein synthesis using a messen- or the A site occupied by cognate or near-cognate tRNA. n D Cate and Gulnara Yusupova and determi- ger RNA template. It mediates the interactions between ned the complete structure of the ribosome. This work largely contributed to the Nobel mRNAs and tRNAs and it catalyses the peptide bond for- Jenner L, Demeshkina N, Yusupova G and Yusupov Prize Award in 2009 to Ada E. Yonath,Thomas mation. Our group has developed methods for x-ray study M (2010) Structural rearrangements of the ribosome at the tRNA proofreading step. A. Steitz and Venkatraman Ramakrishnan. of bacterial 70S ribosome from the extreme thermophilic Nat Struct Mol Biol. in press. Since then, he dedicates himself to the study microorganism Thermus thermophilus and recently for the Jenner L, Demeshkina N, Yusupova G, Yusupov M. of ribosome functioning and translation me- 80S ribosome from the yeast Saccharomyces cerevisiae. Structural aspects of messenger RNA maintenance by the ribosome. chanisms. He became the leader of the Ribo- 1- Crystals of the ribosome from The goal of our group is to study structure and mechanism Nat Struct Mol Biol. 17:555-560. (2010). some Team at the IGBMC in 2001. n of protein biosynthesis in bacteria, yeast and humans. < yeast Saccharomyces cerevisiae Yusupova G, Jenner L, Rees B, Moras D, Yusupov M diffracting to 4.2A resolution. Structural basis for messenger RNA movement on 2- 80S ribosome from yeast the ribosome. Nature. 444:391-394. (2006). Saccharomyces cerevisiae. 40S subunit in blue, 60S subunit in yellow-green. RNA expansion segments in red.

379 From the disease to the gene and vice-versa, pathomechanims and therapeutic strategies

" We explore the genetic bases of physiological and pathological processes, and use genetic mouse models to understand human disorders." B. Kieffer

This Programme brings together nine research are organized at the College de France. groups. Most of them address neural dysfunctions A novel team directed by Yann Hérault has joined and all of the teams share a common interest in recently and addresses the genetic bases of human integrative mouse biology. chromosome 21 deficiencies with a main focus on Six independent teams constitute the human ge- the Down Syndrome. The research addresses phe- netics component founded and animated by Jean- notype-genotype relationships and gene dosage Louis Mandel (Professor of Human Genetics at effects. Experimental strategies involve chromoso- the Collège de France). This component of the mal engineering of the mouse genome and beha- Programme is focused on deciphering the me- vioral analysis of genetic mouse models. This team chanisms underlying several monogenic diseases works in close collaboration affecting the nervous system or skeletal muscle. with human geneticists. Projects include the identification of genes in- The team headed by Brigitte volved and of their mutations, as well as analysis Kieffer explores the function 9 Groups of the normal function of cognate proteins and of peptidic neuromodulatory 24 Staff scientists pathomechanisms responsible for the clinical phe- systems in complex behaviors. notype, as a prerequisite for the development of The principle approaches in- 17 Postdoctoral fellows novel therapeutic strategies. Among the transversal clude gene targeting in mice, 30 PhD students goals shared by several teams are the development pharmacology and behavior, 21 Engineers/Technicians of high-throughput sequencing approaches for fluorescence imaging and elec- the efficient identification of mutated genes and trophysiology. Focus is on the 1 Assistant molecular epidemiology studies in heterogeneous opioid system and associated genetic diseases. Strong links have been established signaling pathways with a major goal being to de- with clinicians (patient recruitment, genotype- cipher the molecular bases of pain control, hedo- phenotype studies) and with patients associations. nic homeostasis and emotional behaviors. This re- Many teams are involved in teaching (Medical search impacts in areas of pathological pain, drug and Life Sciences faculties, College de France) and abuse, stress and mood disorders. This team has bringing science closer to the lay public. Annual strong links with both molecular biologists and meetings on important topics in Human Genetics behavioral psychologists, and has recently esta- Translational blished an international associated laboratory with the Scripps Research Institute (La Jolla, USA). medicine & Mouse models of human diseases : Finally, a cardiovascular component is developing. X-linked mental retardation, Coffin-Lowry Syndrome and A team headed by Jean-Etienne Fabre investigates mental retardation, Bardet-Biedl syndrome, Myotonic dystrophies, Friedreich and other recessive ataxias, Myo- signaling mechanisms leading to atherothrombosis neurogenetics tubularin-associated neuromuscular diseases, Polygluta- and has developed unique mouse models to study mine and Huntington disease, Aneuploidies and Down syndrome, Chronic pain, Drug abuse, Depression, Athe- the disease in vivo. A new team led by Romeo Ric- rosclerosis and thrombosis, Metabolic syndrome. ci has been recruited recently. This team studies Cellular processes involved in pathogenicity : signal transduction mechanisms underlying the Cytoskeletal proteins and membrane trafficking, intracel- n lular cell signaling and kinases, Fe-S cluster biogenesis metabolic syndrome. and cell metabolism, protein/RNA aggregation and cellular toxicity, mRNA transport, DNA repair, neurotransmission and membrane receptors, prostaglandin and leukotriene signaling

81 Physiopathology of the RNA gain-of-

We will pursue the identification of the RNA binding function diseases proteins which are sequestered within the RNA aggregates in RNA gain-of-function patients. Notably, we just found Human Genetics that the FOX1 and FOX2 splicing factors co-localize with CCUG aggregates in DM2 patients. highlights Furthermore, we discovered that the expression of specific mi-RNAs is altered in skeletal muscle and heart of Myotonic Dystrophic patients. We will study the molecular • CUG and CCUG expanded repeats seques- mechanism and the consequences of these alterations. ter the MBNL1 splicing factor. We found that We are currently developing in vitro and in cellulo medium- MBNL1 sequestration in DM patients leads to and high-throughput screens to identify pharmacological alternative splicing of the BIN1 pre-mRNA. In compounds able to reverse the toxic effects of expanded collaboration with Jocelyn Laporte’s team, we future the shaping CUG, CCUG or CGG repeats. If successful, this work found that BIN1 splicing mis-regulation results would constitute a first step toward identifying compounds in T-Tubules and muscle weakness in DM pa- able to reverse the pathogenesis in RNA gain-of-function tients, cell and mouse models. diseases. < Nicolas Charlet-Berguerand • We identified a novel function of MBNL1 as a regulator of micro RNA processing. Conse- 1 quently, the processing of the micro RNA miR- Fight against RNA 1 is altered in DM patients, resulting in cardio- aggregates myocyte dysfunctions. After having spent three years in Paris at probing complexity • We found that expanded CGG repeats seques- The Centre de Génétique Moléculaire (CGM) The RNA gain-of-function diseases are a novel class of ter the SAM68 splicing factor in FXTAS pa- with J. Marie’s team, followed by three human genetic disorders in which expansion of repeated tients, cell and mouse models. Consequently, more years in T. A. Cooper’s laboratory, nucleotides are toxic at the RNA level. These diseases Nicolas Charlet-Berguerand obtained his include Congenital and Adult type 1 and 2 Myotonic specific alternative splicing events regulated by SAM68 are PhD in Paris in 2003 on splicing, applied Dystrophies (DM), Fragile X-Associated Tremor/Ataxia altered in brain samples of FXTAS patients. to human diseases and in particular to Syndrome (FXTAS), Spinocerebellar Ataxia 10 (SCA10) myotonic dystrophies. In 2003, he began and possibly SCA12 and Huntington’s disease-like type • We identified that expanded CGG repeats sequester the his post-graduate research on DNA repair in 2. These autosomal dominant genetic diseases are caused DROSHA/ DGCR8 complex. DROSHA is the enzyme Jean-Marc Egly’s laboratory at the IGBMC. In responsible for pre-micro-RNA processing. Consequently by expanded tri-, tetra- or penta-nucleotide repeats that 2006, he returned to the study of myotonic in DROSHA sequestration, we observed a global altera- dystrophies and created a team dedicated to are transcribed but are not exported, and accumulate in Sellier C., Rau F., Liu Y., Tassone F., Hukema RK., Gat- tion of the micro RNA processing resulting in neuronal toni R., Schneider A., Richard S., Willemsen R., Elliott this topic at the IGBMC. Today, his research pathogenic nuclear RNA aggregates that sequester specific cell death in FXTAS patients. n DJ., Hagerman PJ., Charlet-B. N. Sam68 sequestra- focuses also on Fragile X Tremor Ataxia RNA-binding proteins, leading to molecular changes ulti- tion and partial loss of function are associated with Syndrome (FXTAS) a genetic disorder that mately resulting in the pathological symptoms. splicing alterations in FXTAS patients. EMBO. J. January. In Press. (2010). also reveals, as in myotonic dystrophies, While the general paradigm of these diseases is now es- Dhaenens CM, Schraen-Maschke S, Tran H, toxic RNA aggregates. His team studies tablished, very little is known on the detailed molecular Vingtdeux V, Ghanem D, Leroy O, Delplanque J, 1- Co-localization of DHPR these diseases and searches their associated mechanisms involved in these disorders. Our goal is to Vanbrussel E, Delacourte A, Vermersch P, Maurage CA, Gruffat H, Sergeant A, Mahadevan M, Ishiura (green) and BIN1 (red) in mouse proteins. They also test chemical compounds elucidate the molecular causes of CGG, CUG, CCUG S, Buee L, Cooper TA, Caillet-Boudin ML, Charlet-B isolated muscle fiber. 2- able to suppress the toxic effects and restore and AUUCU RNA toxicity in FXTAS, DM1, DM2 and N, Sablonniere B, Sergeant N. Overexpression of Co-localization of BIN1 MBNL1 fetal isoforms and modified splicing of Tau in (green) and RYR1 (red) in human normal functions in patient cells. n SCA10 patients, respectively. We are particularly focusing the DM1 brain: two individual consequences of CUG myotube. DNA is labeled in blue trinucleotide repeats. on the RNA binding proteins sequestered by these repeats Exp Neurol. 210(2):467-78. (2008). (DAPI) < and the cellular consequences of such sequestration. Charlet-B. N., Feuerhahn S., Kong S., Ziserman H., Conaway J., Conaway R., Egly J.M. RNA polymerase II bypass of oxidative DNA damage is regulated by transcription elongation factors. EMBO. J. 25(23):5481-91. (2006). 2 83 Atherosclerosis We need to keep developing our in vivo tools in order to and thrombosis improve atherothrombosis detection and quantification and are currently developing a method using MRI in collaboration with a German team for both experimental and clinical purposes. Our ultimate goal is to be able to describe by which highlights pathways the whole inflammatory machinery impacts atherothrombosis. When we have delineated the roles of the main prostaglandins and leukotrienes, we will follow • We have developed a new model for studying three directions: in vivo atherothrombosis and have developed • keep investigating the arachidonic pathway through less new methods for investigating vasoconstriction known molecules (lipoxins, epoxy-derived compounds)

in mice, and for quantifying ruptures of athero- shaping the future • investigating the role of the sphingosin/ceramide axis sclerotic plaques. • examining the involvment of cytokines. These studies should allow us to draw a global picture of • We have revealed in our laboratory that mu- the inflammation-thrombosis link.< rine and human plaques produce significant amounts of PGE2 and we identified the PGE2/ EP3 pathway as aggravating atherothrombosis. Jean-Etienne Fabre As a consequence, we demonstrated that bloc- king EP3 allows inhibition of atherothrombosis 1 without altering haemostasis, i.e. without in- Understanding creasing the risk of bleeding. cardiovascular diseases After working for ten years as a Cardiologist probing complexity • Two classical inflammatory vasoconstrictors, in an intensive care unit, Jean-Etienne Fabre Atherothrombosis, the occurrence of thrombosis on athe- LTC4 and TXA2 were used to demonstrate worked for the pharmaceutical industry rosclerotic plaques, is the main cause of myocardial infarc- that vasoconstriction can break atherosclero- for three years at LAFON Laboratories. In tion and stroke, the leading causes of death in developed 1995, he joined J.M. Isner’s laboratory at societies. Atherosclerotic plaques are complex lesions of tic plaques, however only when they are vulnerable. We Tuft University in Boston, (USA) to work the vascular wall, provoked by oxidized lipid deposition showed that only TXA2 is produced by atherosclerotic on angiogenesis. There he studied the plaques. which initiates and maintains local inflammation. Inflam- effects of conversion enzyme inhibitors on mation is itself a complex process that involves numerous angiogenesis. He then joined B.H. Koller’s lipid mediators, and its role in atherothrombosis is poorly • In plaques, we detected fair amounts of leukotriene B4, a powerful chemoattractor for neutrophils. We currently team at the University of North Carolina, delineated. test the hypothesis that neutrophils degrade the fibrous cap Chapel Hill USA. There he showed that To probe this complex picture, we focus our studies on the Magnetic resonance molecular imaging of throm- by releasing their proteases, linking infectious diseases to P2Y1 was an ATP receptor in blood platelets involvement of the arachidonic pathway in atherothrombosis in an arachidonic acid mouse model using an and discovered the existence of LTB4 activated platelet targeted probe. the plaque rupture. We demonstrated that neutrophils can bosis. These molecules have the potential to interfere with Klink A, Lancelot E, Ballet S, Vucic E, Fabre JE, Gon- enter the plaques and release their enzymatic content. n transcellular metabolism. Jean-Etienne also zalez W, Medina C, Corot C, Mulder WJ, Mallat Z, proved that PGE2 promoted thrombosis the plaque vulnerabilization, with the vessel reactivity and Fayad ZA. Arterioscler Thromb Vasc Biol. 30(3):403- with the blood platelet behaviour. We examine in mice 10. (2010). in vivo. He obtained his PhD in 2000 from how each prostaglandin and leukotriene produced by the Strasbourg University. In 2001, he was Antagonists of the EP(3) Receptor for Prostaglandin 1- SEM picture showing the rupture plaque contributes either to the plaque rupture or to lo- E(2) Are Novel Antiplatelet Agents That Do Not Pro- of an aortic murine atherosclerotic contacted by Pierre Chambon and joined long Bleeding. Singh J, Zeller W, Zhou N, Hategen the IGBMC to focus on the link between cal thrombosis through a direct action on platelets. In the G, Mishra R, Polozov A, Yu P, Onua E, Zhang J, plaque. Inside the fracture, activated end, we hope to get a whole picture of the effects of these Zembower D, Kiselyov A, Ramírez JL, Sigthorsson G, platelets are mounting the thrombo- explosive thrombosis and inflammation of Bjornsson JM, Thorsteinsdottir M, Andrésson T, Bjar- tic response. atherosclerotic plaques. n inflammatory mediators on atherothrombosis. nadottir M, Magnusson O, Fabre JE, Stefansson K, Understanding the inflammation-thrombosis relationship Gurney ME. ACS Chem Biol. 4(2):115-126. (2009). will improve the way atherothrombosis is prevented and Vascular wall-produced prostaglandin E2 exacerbates arterial thrombosis and atherothrombosis through also might have important implications in other diseases platelet EP3 receptors. Gross S, Tilly P, Hentsch D, where inflammation is complicated by thrombosis, such Vonesch JL, Fabre JE. J Exp Med. 204(2):311-20 (2007). as cancer and auto-immune diseases. < 2 85 Mechanisms of monogenic forms Gaining a thorough insight into the mechanisms underlying MR will contribute to better understand of mental retardation the processes of normal cognition, notably the molecular events and signaling pathways implicated in Human Genetics activity-dependent local changes that take place in neuronal processes. Our major goals are to : highlights ● define and understand the molecular signals that are involved in controlling mRNA transport and local protein synthesis in neurons, and how they impact • Protein networks: With B. Bardoni, we identi- fragile X pathomechanisms. fied several protein interactors of FMRP, notably the ● understand the mechanisms leading to increased conserved CYFIP proteins, that interact with Rac1 future the haping apoptosis and to AMPA receptor dysfunction in

GTPase and the WAVE complex, key regulators of s Rsk2-KO mice and define the contribution of each cytoskeletal actin remodeling. of these deregulations to the cognitive dysfunction. • Metabolism of neuronal mRNAs (Dr. Hervé Moine): ● define the functional interactions between PAK3, We showed that FMRP binds specifically mRNAs Rsk2 and FMRP. Jean-Louis Mandel containing G(uanine)-quartet motif and also a triple In collaboration with the teams of M. Koenig and stem-loop motif in SOD1 mRNA. We found that André Hanauer J. Laporte, and with the DNA diagnostic lab (Stras- FMRP regulates its own mRNA splicing and the formation of mRNA stress granules. We recently bourg Hospital), we will develop high-throughput Understanding the X-linked showed that the G-quartet motifs present in the 3’ sequencing strategies for gene identification and mental retardations 1 untranslated region of key neuronal mRNAs act as molecular diagnosis in MR. < «zipcode» for their localization to dendrites (unpu- Jean-Louis Mandel earned an MD and MSc blished). and taught genetics at the Strasbourg Uni- probing complexity • Signal transduction: Found increased level of versity before being nominated Professor at cortical dopamine in our Rsk2 deficient mice that Mental retardation (MR), defined as major deficits in -co the Collège de France in 2003. His research in gnitive functions manifesting early in life, originates from is caused by increased tyrosine hydroxylase (TH) activity. We provided evidence that loss of neurons due human genetics has brought major contribu- highly heterogeneous causes, that prominently include tions, notably to our understanding of neuro- to impaired apoptosis and a defect in AMPA neurotransmis- single gene mutations. We study several of these genes muscular genetic diseases. In 1991, his team trying to decipher their function at the molecular, cellu- sion and plasticity might contribute to cognitive dysfunction in Rsk2 KO mice. notably identified unstable mutations invol- lar and central nervous system level, as well as the conse- • Gene discovery: Contributed to the identification of two ving nucleotide triplet repeat expansions res- quence of their deficit in neurons and on cognitive func- major genes mutated in Bardet-Biedl syndrome that defined ponsible for the Fragile X syndrome. From tions in the mouse. We study the FMR1 gene mutated a novel chaperonin family (collaboration with the team of 2002 to 2009, he directed the IGBMC jointly in the Fragile X MR syndrome, the most common cause Pr. H. Dollfus), and to the definition of a new microdele- with Dino Moras. Today, he leads the Genetic of inherited MR, as well as two protein-kinase encoding Bechara EG, Didiot MC, Melko M, Davidovic L, Ben- tion syndrome (del16p11.2) associated to developmental de- Diagnosis Laboratory of the Strasbourg Hos- said M, Martin P, Castets M, Pognonec P, Khandjian genes, RSK2 and PAK3, responsible for X linked forms EW, Moine H, Bardoni B. A novel function for fragile lay and obesity (with the DNA diagnostic lab at Strasbourg pital and is in charge of a team with André of syndromic (Coffin-Lowry) or non-syndromic MR. We X mental retardation protein in translational activation. Hospital, and a large international collaboration). n Hanauer on X-linked mental retardation. PLoS Biol. 7(1):e16. (2009). are also involved in genetic studies of the Bardet-Biedl André Hanauer obtained his PhD in 1989 and syndrome, a pleiotropic ciliopathy, and in genetic diagno- Didiot MC, Subramanian M, Flatter E, Mandel JL, is Associate Professor at the University of Moine H. Cells lacking the fragile X mental retardation sis applications related to MR. Our FMR1 studies focus protein (FMRP) have normal RISC activity but exhibit Strasbourg. In 1996, he identified the gene 1- The G(uanine) quartet structure is a binding altered stress granule assembly. responsible for Coffin-Lowry’s syndrome. on the processes involved in mRNA transport and local Mol Biol Cell. 20:428-37. (2009). site for the Fragile X Mental Retardation Protein translation in dendrites that appear important for synaptic on neuronal mRNAs (left and middle). Presence The team he conducts jointly with Jean-Louis Didiot MC, Tian Z, Schaeffer C, Subramanian M, plasticity. Another focus is the role of signal transduction of a G-quartet-FMRP binding site in the Mandel has made major contributions to the Mandel JL, Moine H. The G-quartet containing FMRP 3’-untranslated region of a mRNA enables its binding site in FMR1 mRNA is a potent exonic splicing understanding of functional and genetic as- pathways that include RSK kinases and PAK kinases and dendritic localization in cortical neurons (green enhancer. Nucleic Acids Res. 36:4902-12. (2008) pects of the Rsk2 gene that is responsible for their role in regulation of neurotransmission and in sy- signal on right panel). Coffin-Lowry syndrome. n naptic plasticity. Knowledge of the precise functions of Marques Pereira P, Gruss M, Braun K, Foos N, Panne- 2- Dendritic spines of hippocampal neurons tier S, Hanauer A. Dopaminergic system dysregulation revealed by actin (red) and Neurabin2 (green) these proteins will contribute to the better understanding in the mrsk2 KO mouse, an animal model of the staining. DAPI staining of the nuclei (blue). of molecular pathomechanisms leading to MR and may Coffin-Lowry syndrome. J Neurochem. 107:1325-34. (2008). open paths towards better treatments.< 2 87 Physiopathology of aneuploidy, gene dosage effect and Down syndrome We plan to focus on three objectives: (1) To address the phenotype–genotype relationship integrating human data; (2) To identify candidate genes and pathways involving dosage sensitive genes responsible for DS and M21 syndromes and (3) To validate new therapeutic approaches highlights in preclinical models with the aim of facilitating the life of people with DS. Furthermore, this study will challenge the balance hypothesis underlying dosage sensitivity suggesting • The Aneuploid zoo: a comprehensive series of mouse model for Aneuploidies linked to human chro- that the stoichiometry of the subunits participating in multi- mosome 21: Homologous and syntenic regions of protein complexes have to be maintained to perform their the Human chromosome 21 (Hsa21) are found biological function. In addition the contribution of the non- on murine chromosomes 16, 17 and 10. We used coding sequences and of the chromosomal organization chromosomal engineering, a strategy we pioneered future the shaping of the aneuploid phenotypes will be carefully evaluated. a few years ago, in order to develop a comprehen- Besides this main project, we are working with human sive series of new mouse models carrying segmen- geneticists to study new aneuploid syndromes in the mouse tal aneuploidies for all the regions that are homo- to develop new strategies to evaluate the contribution of logous to Hsa21 in the mouse. copy number variation to human disease and physiology. < Yann Hérault

• Tackling the genotype-phenotype relationship in DS models: With this aneuploid zoo for Hsa21 we Mice models to study gene 1 are performing a comprehensive phenotypic analy- dosage effects sis for behavior, cognition, morphology and phy- Yann Hérault graduated from the Ecole Nor- probing complexity siology in parallel with gene expression profiling. This strategy led us to identify the consequence male Supérieure and obtained his PhD on Our goal is to identify dosage sensitive genes and we focus of Monosomy 21 on the inflammatory and lung the transcription regulation of clusterin at our interests on a few aneuploid syndromes: the Down functions and the contribution of some telomeric the ENS in Lyon in 1993. He then became syndrome (DS), a frequent aneuploidy affecting 1 new- part of Hsa21 to the DS behavioral impairments. interested in developmental biology and born out of 700, identified as the consequence of Trisomy joined Duboule’s laboratory at the Univer- 21 and the rarer Monosomy 21 (M21), caused by the loss • Contribution of regions and candidate genes to aneu- sity of Geneva in order to study Hox genes of one copy of chromosome 21 (Hsa21). ploid disorders: These studies identified several genetic loci regulation. In 1998, he created the TAMERE Despite prenatal diagnosis, the incidence of DS is still high contributing to DS phenotypes, acting either positively or method, an in vivo chromosome enginee- partly due to the increase in the maternal age and to the negatively on specific functions. This hypothesis allows us ring tool. While working on functional re- to explain part of the phenotypic variability observed in social disparity in the prenatal follow-up. DS is associa- dundancy, he became interested in Down’s DS patients. Our current analysis of the contribution of ted with mental retardation, heart defect and a large panel Lopes Pereira, P., Magnol, L., Sahún Abizanda, I., syndrome, a disease also due to gene dose Brault, V., Duchon, A., Prandini, P., Gruart, A.,, Bizot, additional regions will help to understand further the phy- effects. He created a resource of trisomic of dysmorphologies affecting the face and the skeleton J-C, Chadefaux-Vekemans, B., Deutsch, S., Trovero, F., siopathology of the DS. n mice models for almost the entire Down’s Changes in metabolism and increased frequencies of some María Delgado-García, J., Antonarakis, S.E., Dierssen, M. and Herault Y. A new mouse model for the trisomy syndrome homolog genes in mouse. From pathologies such as leukemia, autism, epilepsy and early of the Abcg1-U2af1 region revals the complexity of 2000 to 2009, he participated and led the onset Alzheimer disease are also observed. the combinatorial genetic coded of Down syndrome Hum. Mol. Genet. 18:4756-4769. (2009). Transgenesis and Archiving of Animal Mo- A few individuals with DS alterations carry a segmental 1- Pyramidal neurons from the dels unit in Orléans. He joined the IGBMC in duplication instead of a complete trisomy. The fifty cases Dierssen, M., Herault, Y., Estivill, X. Aneuploidy: from a Physiological Mechanism of Variance to Down Syn- hippocampus. 2010 as the director of the Mouse Clinic Ins- drome. Physiol. Rev. 89:887-920. (2009). 2- Tackling the hippocampal changes described in the literature are very informative but still not titute and leads a team aiming at mapping enough to understand further the phenotype-genotype re- in DS models involved in learning Duchon, A., Besson, V., Lopes Pereira, P., Magnol, and memory. genotypes / phenotype relations in Down’s lationship. Thus we decided to use the mouse as a model L., and Hérault, Y. Inducing segmental aneuploid mo- syndrome. n saicism in the mouse through Targeted Asymmetric system in order to identify dosage sensitive genes (or other Sister Chromatid Event of Recombination (TASCER). genetic units) that could have a direct or indirect effect on Genetics. 180:51-59. (2008). the DS phenotype. <

2 89 Opioid systems and brain function Our goals are to : ● futher develop site-specific gene knock-out in targeted neurons to identify receptor populations governing addictive behaviors and pain relief. ● continue to study delta and nociceptin orphanin peptide highlights receptors (NOP) as potential therapeutic targets in inflammatory pain, mood disorders, and cognitive deficits. ● explore the role of novel genes in cognitive, emotional and • We have demonstrated that a single receptor addictive behaviors. protein, the mu opioid receptor, mediates both ● continue to investigate the abstinent brain at behavioral, therapeutic and adverse effects of clinically use- genetic and imaging levels. ful opiates. This receptor also mediates rewar- ● develop novel mutant mice with fluorescent receptors

ding properties of other drugs of abuse, and future the shaping together with dynamic neural imaging approaches, to natural rewards. elucidate molecular bases of receptor adaptations and • We have discovered an unexpected role of receptor-receptor interactions in vivo. < delta opioid receptors in anxiety and depression, which has important clinical implications. We Brigitte Kieffer 1 have uncovered unanticipated and opposing contributions of mu and delta receptors in self- control, opening novel avenues towards unders- Specialist in opioid receptors probing complexity tanding behavioral inhibition. As Assistant Professor at the University of • We have identified novel genes, whose role in Strasbourg, Brigitte Kieffer isolated, in 1992, addictive behaviors is yet unknown. Opiates have been used for thousands of years for their the first gene encoding an opioid receptor • We have created knock-in mice where delta pain-relieving and rewarding properties. Opiates produce paving the way towards understanding ge- opioid receptors are directly visible in vivo. This their potent effects by activating opioid receptors in the netic bases of opioid-controlled behaviors. brain, thereby highjacking a complex neuromodulatory Using gene targeting in mice she demons- system. Opioid receptors (mu, delta, kappa and nocicep- trated that a single receptor protein, the tine/orphanineFQ) are normally stimulated by endoge- unique tool has allowed us to describe receptor anatomy mu opioid receptor, mediates both potent throughout the nervous system at cellular and subcellular nous peptides to control pain and stress responses, as well analgesic and addictive effects of morphine. levels, and to investigate real-time receptor trafficking in She also discovered anxiolytic and antide- as emotional and addictive behaviors. live neurons and to understand behavioral desensitization Our goal is to tackle the role of opioid and related neu- mechanisms. This is a ground-breaking approach in the pressant activities of the delta opioid recep- ropeptide systems in brain physiology, as well as neuro- field of G protein-coupled receptor biology and drug dis- tor. logical and psychiatric disorders. We address molecular Olmstead C., Ouaggazzal A-M. and Kieffer B. L. Mu and covery. n Her work has important implications in basic delta opioid receptors oppositely regulate motor impulsivity neurosciences and the biomedical commu- mechanisms underlying the development of chronic pain in the signaled nose poke task Cited in the Editor’s choice and associated affective disorders and investigate molecu- section of Science PLoS ONE 4(2):984-985. (2009). nity. From 1994 to 2006 she was a Professor at the Faculty of Pharmacy in Strasbourg lar adaptations that develop under repeated exposure to Scherrer G, Imamachi N, Cao YQ, Contet C, Mennicken F, and is currently a Research Director at In- drugs of abuse, and contribute to craving and relapse. We O’Donnell D, Kieffer BL and Basbaum AI. Dissociation of the opioid receptor mechanisms that control mechanical and serm. She has also been a visiting Professor explore potential roles of these receptors in other areas of thermal pain. Cell 137:1148-59. (2009). at University of California, Los Angeles since psychiatric disorders, and identify neurons where the re- 1- Fluorescently-labelled opioid Pradhan A., Becker J., Scherrer G., Tryoen-Toth P., Filliol D., 1998. She joined the IGBMC with her team in ceptors operate to control behavioral responses. Finally, Matifas A., Massotte D., Gavériaux-Ruff, C and Kieffer B. L. receptors visible in the brain In vivo delta opioid receptor internalization controls behavio- hippocampus of genetically 2001. In 2004, she received the Loundsberry we use genome-wide approaches to discover novel mole- ral responses to agonists. PLoS ONE 4(5):e5425. (2009) engineered mice. Award from joined French and US Acade- 2- Direct opioid receptor cular targets for drug abuse research. mies of Science and became a EMBO Mem- Scherrer G., Tryoen-Tóth P., Filliol D., Matifas A., Laustriat D., visualization in live neurons Our laboratory uses gene targeting approaches in mice Cao Y. Q., Basbaum A. I., Dierich D., Vonesh J.-L., Gavériaux- ber in 2009. n (knockout, conditional knockout and knock-in), behavio- Ruff C. and Kieffer B. L. Knock-in mice expressing fluorescent delta opioid receptors uncover G protein coupled ral analysis, pharmacology, as well as receptor and cellular receptor dynamics in vivo imaging to achieve these goals. < Proc. Natl. Acad. Sci. USA. 103:9691-6. (2006) 2 91 Recessive ataxias

The publication of the first and subsequent drafts of the human genome sequence has allowed the identification of an increasing number of genes and mutations Human Genetics causing mendelian disorders. It has also revealed part of the incredible complexity of these disorders, due to highlights underestimated genetic and phenotypic heterogeneity. A future impact of the human genome project will be the availability of personalized human genome sequencing (2nd • Identification of the genes defective in Frie- and 3rd generation high-throughput sequencing methods). dreich ataxia and ataxia due to Coenzyme Q10 In addition to raising great concerns about ethical issues, deficiency, both coding for novel mitochondrial this possibility paves the way to molecular diagnosis for proteins (frataxin and ADCK3) supporting as- clinical practice of (almost) any mendelian disorder. Our

sembly of components of the respiratory chain. future the shaping aim is to develop applications of the next generation high- Construction and characterization of the first throughput sequencing for diagnostic purposes and further murine and cellular models of Friedreich ataxia unravel the complexity of the disorders for which DNA for preclinical drug screenings. samples of patients are referred to us.< • Identification of novel forms of inherited Michel Koenig ataxias that associate cerebellar degeneration, sensorimotor peripheral neuropathy and oculo- A crossed career between 1 motor apraxia. Identification of the correspon- medicine and genetics for ding genes, coding for novel nuclear proteins, aprataxin and senataxin, involved in DNA repair rare diseases diagnosis probing complexity and RNA maturation. Michel Koenig trained in medicine and biology. In 1986, he obtained a PhD in genetics Recessive progressive ataxias represent a heterogeneous • Identification of the genes defective in Giant on the human X and Y chromosomes carto- group of neurological disorders characterized by the dege- Axonal Neuropathy, Ataxia with isolated Vita- graphy. He went on to pursue his post-doc neration of the cerebellum and/or the spinocerebellar and min E Deficiency, Marinesco-Sjögren Syndrome with Louis Kunkel’s team at the Harvard Me- posterior columns of the spinal cord. and Salih Ataxia, coding for cytosolic proteins involved in dical School, USA until 1989. At that time, Albeit ataxia is the prominent symptom, recessive pro- various functions of membranes and cytoskeleton. this team had just discovered the Duchenne gressive ataxias often combine additional features such as • We identified all disease genes by the pioneering use of muscular dystrophy gene and Michel Koenig peripheral neuropathy, pyramidal and/or extrapyramidal homozygosity mapping and high density genetic marker contributed to its characterization. In 1990 he signs, nystagmus, oculomotor apraxia, ophthalmoplegia, M. Assoum, M.A. Salih, N. Drouot, D. H’Mida-Ben analysis. Their identification had immediate and impor- Brahim, C. Lagier-Tourenne, A. AlDrees, S.A. Elmalik, obtained his MD and integrated Jean-Louis optic atrophy, deafness, mental retardation, and epilepsy, T.S. Ahmed, M.Z. Seidahmed, M.M. Kabiraj, M. Koenig tant applications for diagnosis of recessive ataxias in clini- Mandel’s team to work on recessive ataxias. as well as non-neurological features. Due to these asso- Rundataxin, a novel protein with RUN and diacylglycerol cal practice. n binding domains, is mutant in a new recessive ataxia. The gene responsible for Friedreich’s ataxia ciated signs and symptoms, differential diagnosis is often Brain. (In press) (2010). was identified in 1996 and enabled the deve- difficult with related disorders such as spastic paraplegias M. Anheim, B. Monga, M. Fleury, P. Charles, C. Barbot, M. lopment of mouse models. As a result, many with cerebellar involvement, sensory ataxic neuropathies, Salih, J.-P. Delaunoy, M. Fritsch, L. Arning, M. Synofzik, L. other recessive ataxia genes were identified. Schöls, J. Sequeiros, C. Goizet, C. Marelli, I. Le Ber, J. Koht, congenital ataxias, metabolic ataxias, periodic ataxias, J. Gazulla, J. De Bleecker, M. Mukhtar, N. Drouot, L. Ali-Pa- Since 1996, he works with the Strasbourg cerebellar hypoplasias, and the CACH and Joubert syn- cha, T. Benhassine, M. Chbicheb, A. M’Zahem, A. Hamri, B. Hospital and his discoveries are now used Chabrol, J. Pouget, R. Murphy, M. Watanabe, P. Coutinho, 1- Expression of gene identified in dromes. We have opted to tackle the very high clinical and M. Tazir, A. Durr, A. Brice, C. Tranchant and M. Koenig. Cos cells (electronic microscopy) by neurologists for rare genetic disorder dia- genetic heterogeneity of the recessive ataxias by linkage Ataxia with oculomotor apraxia type 2: clinical, biological 2- Gene Identification, linkage, gnoses. Michel has led his own team at the and genotype/phenotype correlation study of a cohort of 90 sequencing & light Scanner n studies of large consanguineous families referred to us by patients. Brain. 132: 2688-2698. (2009). IGBMC on recessive ataxias since 2002. collaborating neurologists worldwide. Today, at least 15 C Lagier-Tourenne, M Tazir, LC López, CM Quinzii, M genes of recessive progressive ataxias have been identified, Assoum, N Drouot, C Busso, S Makri, L Ali-Pacha, T Ben- hassine, M Anheim, D Lynch, C Thibault, F Plewniak, L of which seven were identified by or in collaboration with Bianchetti, C Tranchant, O Poch, S DiMauro, JL Mandel, our group. Mutations of these genes account for about 50 MH Barros, M Hirano, M Koenig. ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associa- to 60% of the cases, indicating that many rare forms of ted with Coenzyme Q10 deficiency. recessive ataxias remain to be identified. < Am J Hum Genet. 82:661-672. (2008). 2 93 Mechanisms of In order to better understand the molecular basis of severe neuromuscular diseases and to propose possible neuromuscular diseases therapeutic targets and approaches, we aim at: ● identifying additional genes implicated in neuromuscular Human Genetics diseases through the development of high-throughput sequencing strategies. Such approaches are at the heart of highlights the future personal medicine based on the knowledge of our own genome. ● characterizing the link between membrane remodeling • We identified and characterized the myotubu- and organelle positioning and the implication of the larins family, phosphoinositides phosphatases cytoskeleton. This work should point to novel pathways mutated in several neuromuscular diseases and implicated in the late maturation and structural maintenance

implicated in endocytosis and autophagy. future the shaping of skeletal muscle fibers. ● using viral transfer in mouse to generate and rescue • We identified the first mutations in amphiphy- muscle weakness. sin 2 (BIN1), previously described as a tumor ● validating confocal macroscopy for non-invasive suppressor, in autosomal centronuclear myopa- monitoring of muscle in mammals. < thy. Mutations either impact on its membrane remodelling property or disrupt its binding with Jocelyn Laporte dynamin 2, another protein mutated in such diseases. Interdisciplinarity for the 1 study on neuromuscular • Using a mouse model for X-linked centro- diseases nuclear myopathy, our group showed that the probing complexity muscle weakness is linked to T-tubules and cal- After completing studies in technical We study rare and severe neuromuscular disorders caused cium homeostasis defects. formation at the Strasbourg School of by mutations in proteins affecting organelles and mem- Biotechnology (ESBS), Jocelyn Laporte did brane trafficking. Our principle focus is on three families his PhD with Jean-louis Mandel and identified of proteins that regulate or are regulated by membrane • Together with the IGBMC imaging platform, we vali- in 1996 the myotubularin gene (MTM1) lipids: the phosphoinositide phosphatase myotubularins, dated integrated methods for high pressure freezing and involved in centronuclear myopathies. He the membrane remodelling amphiphysins and the mem- correlative light-electron microscopy, linking dynamic live became a team leader at the IGBMC in brane fissioning GTPase dynamins. Both myotubularins cell imaging to 3D ultrastructure. 2007. The same year, his team brought to and dynamin 2 are mutated in centronuclear myopathies, light the involvement of amphiphysin 2 in • We developed and transferred most of the existing mole- severe congenital myopathies characterized by mislocali- myopathies. His team’s research is based cular diagnostic strategies for the different forms of centro- on a interdisciplinary approach from human sation of nuclei and in Charcot-Marie-Tooth peripheral nuclear myopathies to the Genetic Diagnosis lab at Stras- genetics to therapeutic approaches through neuropathies, suggesting a common mechanism. Spiegelhalter C, Tosch V, Hentsch D, Koch M, Kessler bourg Hospital. n M, Schwab Y, Laporte J. From dynamic live cell imaging protein functional analysis and animal While focusing on these genetic diseases, our approaches to 3D ultrastructure: integrated methods for high pres- are multidisciplinary and encompass the identification of sure freezing and correlative light-electron microscopy. models development. PLoS ONE 5(2):e94. (2010). the implicated genes by high-throughput sequencing, the Currently his team participates in the validation of new sequencing and imaging study of the molecular and cellular functions of these pro- Al-Qusairi L, Weiss N, Toussaint A, Berbey C, Messad- deq N, Kretz C, Sanoudou D, Beggs AH, Allard B, Man- 1- Co-localisation between the early technologies. The team’s research is both teins in cells and in C. elegans, the validation of mamma- del JL, Laporte J, Jacquemond V, Buj-Bello A. Defective endosome antigen 1 protein (green) fundamental and applied and they work lian disease models, and the use of viral vectors (AAVs) for excitation-contraction coupling in muscle fibres lacking and the Phosphoinositide 3-mono- myotubularin phosphoinositide phosphatase. Proc Natl phosphate detected with a biosensor closely with the laboratory for genetic pathophysiology studies and preclinical therapeutic trials. Acad Sci U S A. 106 (44):18763-18768. (2009). (red). DNA in blue. disease diagnosis at the Strasbourg In parallel, we study the function of these proteins in ske- Nicot AS, Toussaint A, Tosch V, Kretz C, Wallgren-Pet- 2- Homozygous mutation of the Hospital. n letal muscle under normal and pathological conditions tersson C, Iwarsson I, Kingston H, Garnier JM, Bianca- BIN1 gene in a consanguineous lana V, Oldfors A, Mandel JL, Laporte J. Mutations in through the development of novel imaging methods (cor- family. Above : chromatopherogram, amphiphysin 2 (BIN1) disrupt interaction with dynamin below : pedigree of the affected relative microscopy and in vivo imaging) in close contact 2 and cause autosomal recessive centronuclear myopathy. Nature Genetics. 39:1134-1139. (2007). family. with the IGBMC platforms. < 2

95 Biology and physiology of recessive ataxia The objectives of the laboratory are to further elucidate the molecular mechanism underlying neuronal dysfunction in FRDA and XLSA/A, two recessive ataxia linked to Fe-S cluster Human Genetics deficit and ARCA2, a newly discovered recessive ataxia linked to Coenzyme Q10 deficit. We will develop animal highlights models for ARCA2 and XLSA/A, as well as neuronal cellular models for the three diseases. In particular, the recent technical advances in the generation of induced pluripotent • Through conditional knockout approaches, stem cells (iPS) from somatic cells provide a powerful tool we have developed the first mouse models for to create disease-specific cellular models. Furthermore, to FRDA, which reproduce important progressive uncover common pathways among recessive ataxia leading features of the human disease. With these mo- to neuronal dysfunction, comparative transcriptomic and

dels, we have shown that the primary event in future the shaping proteomic analysis will be performed. In parallel, we will the disease is the deficiency in mitochondrial continue functional studies to further unravel the molecular Fe-S proteins followed by a secondary mito- steps of Fe-S biogenesis and coenzyme Q10 biogenesis, two chondrial iron accumulation. More recently, we fundamental pathways in the mitochondria. < have provided the first direct evidence that frataxin is necessary for the proper assembly of ex- Hélène Puccio tra-mitochondrial Fe-S proteins in mammalian tissues, both cytosolic and nuclear. 1 Understanding the molecular mechanisms of probing complexity • By combining in vitro and in vivo approaches, recessive ataxia we have recently demonstrated that frataxin The laboratory is dedicated to unraveling the causes and interacts with the preassembled core complex After obtaining her PhD in Genetics from mechanisms of progressive recessive ataxias, which are involved in the early steps of de novo Fe-S bio- Harvard University, USA in 1998, Hélène neurodegenerative disorders that affect the cerebellum genesis, providing a new understanding of the Puccio joined the group of Michel Koenig sequential steps of Fe-S biosynthesis in vivo. and/or the spinal cord. Recessive ataxias represent a heat the IGBMC to work on the molecular terogeneous set of severely disabling neurological disor- • We have developed different cell models based either pathogenesis of Friedreich ataxia (FRDA). ders estimated to affect 1/20,000 individuals in Europe. on antisense strategy reproducing the quantitative defect In 2001, she was appointed Inserm research Friedreich ataxia (FRDA), the most common recessive found in patients or on expression of frataxin carrying di- associate and has since been the principal ataxia, is characterized by progressive gait and limb ataxia sease-causing mutation. These models exhibit proliferation investigator on the FRDA project. Her associated with hypertrophic cardiomyopathy and an in- defects associated with specific biochemical features of the research focuses on understanding the disease and are therefore good models for drug screening. creased incidence in diabetes. The disease is due to severely physiopathology of FRDA through the reduced levels of frataxin, a highly conserved mitochon- development of animal and cellular models Schmucker S and Puccio H. Understanding the • We have shown that idebenone, a CoQ10 analog in cli- drial protein thought to be involved in multiple iron-de- molecular mechanisms of Friedreich’s ataxia to nical use, has a significant effect on the cardiac function and on the development of therapeutic pendent mitochondrial pathways. In particular, frataxin is develop therapeutic approaches. Human Molecular and the life span of the murine cardiac model. n approaches. Genetics. 19(R1):R103-10. (2010). proposed to be involved in iron-sulfur (Fe-S) cluster bio- She was awarded the Pediatric Pathology Calmels N., Schmucker S., Wattenhofer-Donzé M., Prize in 2005 and also received the label synthesis. Fe-S clusters are critical redox active prosthetic Martelli A., Vaucamps N., Reutenauer L., Messaddeq M., Bouton C., Koenig M., Puccio H. The first cellular "Equipe FRM". In 2007, she obtained the groups that are present in proteins involved in numerous 1- models based on frataxin missense mutations that Mitochondrial dysregulation and prestigious Young Investigator ERC award, essential cellular processes ranging from nuclear genome reproduce spontaneously the defects associated iron accumulation in cardiac tissue stability, protein translation to mitochondrial metabolism. with Friedreich ataxia. PlosOne. 4(7):e6379. (2009) from mouse model of Friedreich and in 2008 she received the Dr. Jean Toy ataxia. Prize from the Academy of Sciences and was Mitochondria contain a complex system for assembly of Schmucker S, Argentini M., Carelle-Calmels N., Mar- 2- Human neurons (red: bIII-tubu- promoted Inserm Research Director. n Fe/S metal centers and their insertion into proteins. In ad- telli A, Puccio H. The in vivo mitochondrial two-step maturation of human frataxin. lin) and astrocytes (green: GFAP) dif- dition to unravelling the pathophysiology of the disease, Human Molecular Genetics. 17(22):3521-31. (2008). ferentiated from induced pluripotent we aim to understand the molecular mechanism of mam- stem cells (iPS) derived from adult Martelli A., Wattenhofer-Donzé M., Schmucker S., fibroblasts. malian Fe-S cluster biogenesis, with a particular interest Bouvet S., Reutenauer L., and Puccio H. Frataxin is essential for extramitochondrial Fe-S cluster proteins in the role of frataxin. Our strategy combines human ge- in mammalian tissues. netics, biochemistry, cell biology and animal models. < Human Molecular Genetics. 16(22):2651-8. (2007). 2 97 Pathogenic mechanisms

We aim to understand the relationship between the of polyglutamine expansion diseases polyQ structure, aggregration and toxicity and are using aggregation modulators as tools to delineate the aggregation Human Genetics mechanisms and combine theses with biological, structural and computational approaches. highlights In the SCA7 mouse PolyQ toxicity induces not only photoreceptor death involving apoptotic and non-apoptotic mechanisms but also proliferation, which may partially • Polyglutamine expansion and short polyglu- compensate for photoreceptor loss. We are studying tamine tract have similar structural properties the molecular mechanisms underlying these exceptional in vitro. This contradicts the hypothesis that degenerative and potentially regenerative processes in this polyglutamine can adopt a toxic structure only model.

beyond a specific length and rather suggests that future the shaping To further understand the mechanisms underlying CAG toxicity increases with polyglutamine length and instability in HD, we combine in vitro and in vivo approaches manifests when cellular mechanisms against and investigate the role of Parp1, which coordinates BER toxicity are overwhelmed. (Base Excision Repair) by facilitating the remodeling of chromatin and the recruitement of BER factors to DNA • Our SCA7 transgenic mouse recapitulates Yvon Trottier lesions. < the retinal degeneration affecting the patients. Expression profile analysis of SCA7 mouse re- Understanding the 1 tina reveals that transcriptional alterations com- Huntington disease probing complexity promise the photoreceptor differentiation status and function. Originally from Canada, Yvon Trottier Polyglutamine diseases are ten adult-onset genetic disor- obtained his PhD in 1992 at Laval University ders that result in the degeneration of selected brain areas. • Polyglutamine aggregation triggers a cellular in Québec. In 1992 he joined the laboratory stress response involving the activation of AP1 They are caused by an expansion of unstable CAG trinu- of Jean-Louis Mandel, who had just transcriptional pathway in the SCA7 mouse cleotide repeats coding for toxic polyglutamine (polyQ) uncovered the disease-causing triplet expansions in ubiquitously expressed disease proteins. Un- retina. AP1 activation correlates with repression of genes repeat expansions, to work as a post- derstanding the molecular and cellular mechanisms un- involved in photoreceptor function. Inhibiting AP1 in the doc on Huntington’s Disease. In 1995, he derlying polyQ toxicity and neurodegeneration is essential SCA7 mouse delays the retinal phenotype. characterized an antibody able to detect to develop effective treatments against these incurable di- polyglutamine expansions and used it as • Stoichiometry of the DNA repair proteins DNA Po- seases. To this end, our strategy combines biochemistry, a tool to identify two more polyglutamine lymerase ß and Flap endonuclease 1, which are involved biophysics, cell biology and analysis of mouse models disorders. In 2002, he studied the in Base Excision Repair (BER), contributes to the tissue of two polyQ disorders: Huntington’s disease (HD) and selectivity of CAG instability in HD mice. n proteolysis mechanism of the Huntington’s Spinocerebellar ataxia type 7 (SCA7). Our plans are : 1) Yefimova MG, Messaddeq N, Karam A, Jacquard C, disease protein. His recent work on to study the interaction and aggregation properties of Weber C, Jonet L, Wolfrum U, Jeanny JC, Trottier Spinocerebellar ataxia type 7 enabled him Y. Polyglutamine toxicity induces rod photoreceptor proteins harboring polyQ expansion to understand why division, morphological transformation and death in to show that in response to polyglutamine Spinocerebellar ataxia 7 mouse retina. toxicity, neurons undergo different cell fates they become neurotoxic ; 2) to study signaling pathways Neurobiol Dis. (in press) (2010). and gene expression to understand how affected neurons including dedifferentiation, proliferation and 1- SCA7 retinal section showing Goula AV, Berquist BR, Wilson DM 3rd, Wheeler VC, death. Since 2007, he has led his own team respond to toxic stress and how they degenerate; 3) to in- Trottier Y, Merienne K. Stoichiometry of base excision aggregates (green) of polyglutamine- vestigate the mechanism of instability of CAG repeats in repair proteins correlates with increased somatic expanded ataxin-7 in photoreceptor at IGBMC on pathogenic mechanisms of CAG instability in striatum over cerebellum In Hun- n HD, which generates larger expansions associated with nuclei (red, left). polyglutamine expansion diseases. tington’s disease transgenic mice. 2- Electron micrograph showing PLoS Genet. 5(12):e1000749. (2009). increased protein toxicity and is particularly important in structured amyloid-like fibers formed the striatum, the primary target in HD. Our ultimate goal Klein F, Pastore A, Masino L, Zeder-Lutz G, Nieren- by polyglutamines in vitro. is to identify effective treatments for polyQ disorders. < garten H, Oulad-Abdelghani M, Altschuh D, Mandel JL, Trottier Y. Pathogenic and non-pathogenic polyglutamine tracts have similar structural properties: towards a length dependent toxicity gradient. J. Mol. Biol. 371:235-244. (2007). 2 99 MOUSE CLINICAL INSTITUTE

¨ The mouse model has become the premier model to better understand the fundamental mechanisms responsible for complex biological phenomena.¨ Y. Hérault vior, reproduction, morphology etc.. The ICS plays a central role in large-scale infrastructures, both on a national level with CELPHEDIA and on a European level through the European Infrastructure Programme INFRAFRONTIER. Likewise, the ICS is a major player in various European funded programs oriented towards mouse genetics such as EUComm, EUmodic, EMMA. In joining the Interna- IBiSA tional Mouse Phenotyping Consor- ISO 9001/2008 in progress tium, the ICS contributes to de- 6 years of partnership with cipher mammalian gene functions pharmaceutical companies in order to better understand hu- The Institut Clinique de la Souris (ICS) is a research in- More than 250 mutagenesis man physiology and disease. or phenotyping projects frastructure of excellence for translational research and The services of the ICS will ulti- per year functional genomics. Founded in 2002 by Pierre Cham- mately help the scientific commu- Partner in 14 EU funded bon and operated by Inserm, CNRS, and the Univeristy nity to use the mouse to develop a projects since 2002 of Strasbourg, it provides a comprehensive set of specia- complete functional annotation of 110 Staff members lized services to academic and industrial users and is a the human genome and to employ major player in the European post-genomic era programs. this to better understand human The close interaction with the IGBMC strongly contri- diseases and their underlying physiological and patholo- butes to the development and design of new techniques gical basis. < and functional assays. The ICS combines the capacity of generating mutant mice on a large scale with a high-throughput and comprehensive phenotypic analysis of the animals. The Institute’s

phenotyping platforms are adapted for the study of ge- The ICS is a national infrastructure closely linked to the IGBMC. Its mission is to : netically engineered mouse models and genetic reference ● provide a service platform combining a large scale ca- populations but can also be used for preclinical studies pacity for generating mouse mutants followed by subse- including the validation of therapeutic targets as well as quent high-throughput and comprehensive phenotypic analysis of the animals Institut CLINIQUE pharmacological and toxicological studies in the mouse. ● facilitate access to engineering, analysis and distribu- The three highly interactive departmentsGenetic Enginee- tion of mouse models for the scientific community DE LA SOURIS ring and Model Validation, Phenotyping and Mouse Facility ● initiate and advance relevant in-house research and generate approximately 200 genetically modified mice per development programs to support the activities of ICS in the domains of mutagenesis, transgenesis, phenoty- year. Phenotypic analysis cover hematology, immunology, ping, bioinformatics, and data analysis. inflammation, blood chemistry, metabolism, cardiovascu- ● promote training both internally and for users in order lar, respiratory, sensory organs, cognition, learning, beha- to guarantee the most efficient procedure in compliance with ethics and animal welfare. ● be a reference centre for mouse functional genomics and preclinical research

101 bioinformatiCS

¨ Previously, we worked mainly on genome sequences, however today the field of investigation has widened. There is not only one, but many Bioinformatics.¨ F. Plewniak

rable environment to develop its expertise both in biology and computer science. The dual competence of its staff members permits the offering of a high standard of expertise in bio- analysis, as well as database or software development services. For all projects we guarantee that the underlying ISO 9001 scientific problem is properly understood and addressed using IBiSA appropriate solutions. 35 projects/year The platform is a member of the Réseau National des plate-formes 5 Staff members Bio-Informatiques (ReNaBi) and The IGBMC Bioinformatics technical plat- was recognized as an operational form platform provides bioinformatics re- platform by IBiSA (Infrastruc- sources including up-to-date databases, tures Biologie Santé et Agrono- bioinformatics software, efficient computer mie) in 2009. The Bioinformatics platform systems, large storage capacity and expertise Quality Management System according to capable of addressing biological problems ISO 9001 norm was certified in June 2007.< from basic sequence analysis to integrative and high-throughput computational biology. In sympathy with the IGBMC’s research interests, we are mainly involved in comparative Access to bioinformatics resources The bioinformatics resources provided by the platform in- genomic and bioinformatic studies of trans- clude: cription related to research on human patho- • Over 30 public databases (Genbank, Uniprot, Protein Data platforms logies, such as cancer or genetic diseases. This Bank,Unigene,...) includes promoter analysis, for example, phy- • All prokaryotic complete genomes available from the NCBI logenetic foot-printing, in relation to trans- • 41 selected eukaryotic complete genomes criptomics data analysis, as well as studies of • Locally developed and third party software evolutionary events or mutation effects in hu- Expertise in bioinformatics and bio-analysis man and animal model organisms. This activity includes both short-term consultancy projects and the participation of the platform as a partner to long- The platform is located within the IGBMC term funded projects. premises in close proximity to the biologists. Research and development The platform benefits from a particularly favo- Apart from the above services, an important mission of the platform is to develop innovative solutions for bioinformatics and bio-analysis questions.

103 HIGH-THROUGHPUT cell-based SCREENING imaging and microscopy

"High throughput cell-based screening technologies accelerate the phase ¨ Over 20 years, the imaging service has acquired a unique expertise. of identification of genes responsible for a particular phenotype or response, Inventive and creative, it develops prototypes that can be industrialized. ¨ J-L Vonesch by delivering an immediate functional characterization" L. Brino

notype analyses. So far, we have performed more The electron microscopy group (4 engineers and a than ten RNAi-based screening projects and we are technician) has extensive experience in studying the currently investigating the chromatin function in ultrastructure of various cell types and tissues in nor- DNA damage repair processes. Our siRNA libra- mal and pathological conditions. With an expertise ries target diverse human and mouse gene subsets in sample preparation ranging from conventional such as the kinome/phospha- techniques to the use of cryo- tome or the druggable genome IBiSA in process methods, such as high pressure IBiSA and we have recently acquired freezing and freeze-substitution, ISO 9001 100 projects per year a Qiagen human genome-wide the facility can process almost any in process 40 imaging systems siRNA library. The platform is type of biological sample, from cellular extracts to tissue biopsies. • 10 confocal developing a Quality Manage- 65,000 analyses microscopes ment System (ISO9001 norm) in 2009 Besides the ultrastructural analy- • 2 TEM, The Imaging Center was created in 1992 to deal sis, the group also performs pro- • 1 SEM and has been identified by IBiSA 5 Staff members with the increasing demands and the complexity of tein localization at high resolution for the coming round of quali- 25-30 publications biological imaging at the IGBMC. Recognized as an by immuno EM labeling. The IGBMC High-Throughput Cell-based fication and support. The plat- per year IBiSA platform, this facility is not only devoted to The two groups also offer com- Screening platform, created in 2006, is one of the form is largely open to French 13 Staff members the IGBMC but reaches out to both the local and bined and integrated approaches major high-throughput RNAi screening facilities in and foreign academic laboratories. < French scientific community. The Imaging staff,- or such as correlated light and elec- France. We participate in the global project realiza- ganized as two groups for light and electron micros- tron microscopy.< tion beginning with: cellular process optimization, copy, has complementary expertise and experience assay miniaturization, image analysis and develop- that ranges from biology and physics to computing. ment even before the screening campaign is star- This experience and expertise allows the platform to ted. Primary and secondary phenotype screening The Imaging Center is an open facility that offers integra- • Expertise in mammalian cell transfection and RNAi offer a wide variety of equipments and approaches and validations are performed by the facility. We screening design. tive imaging approaches to trained and untrained users: both in terms of service, teaching and development. • Development of new tools and protocols in collaboration are equipped with a BSL2+ biologicalcontainment • Participates in the preparation of applications for The light microscopy group (7 engineers) offers an with research teams, to address challenging biological facility for mammalian cell culture, high-through- research projects that aim to conduct phenotypic screening. open access to a range of imaging systems, such questions, such as micromanipulation and live imaging, put cell transfection and post-processing cell mani- as epifluorescent and confocal microscopes and photo-ablation, correlative light and electron microscopy. pulation. Currently, assay read-outs are performed • Develops innovative high-throughput cell-based ap- macroscopes. Image analysis stations are also offered • Further development of the ultra-wide-field photonic either on the fully automated GE Life Sciences plications. imaging and confocal macroscope designed at the Cen- to the users of the platform. The specialists of the ter, to visualize and quantify biological processes at the INCELL1000 analyzer or the Berthold High • Participates in the development of high-content ana- group assist the researchers in more complex experi- centimeter scale. throughput MITHRAS LB940. Together with lysis solutions in biostatistics and bioinformatics. ments where specific expertise is needed, such as F- • Industrial partnership (Leica Microsystems, COMAT). the IGBMC Bioinformatics platform, we have • Strengthens and accelerates the approach “From techniques (FRAP, FRET/FLIM). More than 80% • Continuum of imaging techniques between light and developed a robust biostatistical tool (RReportGe- Genes to Drugs”. of the experiments in the facility are performed on electron microscopy (confocal microscopy and macrosco- nerator software) for the analysis of large cellular py, infra and far-red two photon microscopy, fast confocal living samples with specific setups tailored for func- multiparameter datasets as well as downstream microscopy, ultrastructural analysis). tional imaging, time lapse microscopy, and fast mul- data enrichment solutions for comprehensive phe- • Image processing and analysis tiphoton and confocal imaging. • Teaching programs and training workshops at the Univer- sity with national and international organizations.

105 MICROARRAYs & DEEP SEQUENCING STRUCTURAL BIOLOGY & GENOMICS

" Our techniques allow the study of genetic and molecular differences ¨ This platform is the technological backbone for the production between the normal and pathological states." C.Thibault and characterization of functional complexes and will be an essential player in the future challenges in structural cell biology.¨ D. Busso

projects. Moreover, the tight synergies between publications as of February 2010). The plat- the SBGP and the IGBMC facilities (Bioinfor- form has been involved in several large na- matics, Mass Spectroscopy, Cell Imaging) create tional programs, such as the Tumor Identity an attractive scientific center for academic and Card (CIT) program from the Ligue Natio- industrial researchers. Thus, providing integrated nale Contre le Cancer, and the structural and functional studies RESOGEN program from the on systems that are important to French Center for Genomic ISO 9001 IBiSA the understanding of biological Research. It has also been qua- IBiSA pathways and human diseases. HTP procedures lified as ¨ National platform ¨ A major commitment of the by the ¨ Réseau Inter-Organism 150 Projects Quality statements SBGP is to implement cutting ¨ (RIO) and also by the IBISA per year edge technologies and to deve- European networks since 2003. Lastly, because the 11 Staff members lop methodologies for protein platform has heavily invested in production and characterization 8 Staff members The IGBMC Microarray and Deep Sequen- quality, it became one of the first that contribute to the technolo- cing platform, created in 2000, is one of the French technology platforms to gical backbone of the Strasbourg major microarray facilities in France. We are obtain the ISO9001 certificate The focus of the Structural Biology and Genomics node in the European Integrative equipped with Affymetrix and Agilent mi- in 2007, which was renewed in 2010. < platform (SBGP) is to provide technological re- Structural Biology Infrastructure croarray technologies and we run 1,500 to sources to investigate complex biological systems, Program (INSTRUCT). < 2,000 arrays annually for a wide variety of that range from single proteins to assemblies of transcriptomic and genomic applications. proteins and nucleoprotein complexes. Ultima- In October 2008, the platform invested in tely this will contribute to an integrated view of The SBGP offers high-level support to its users, ranging high-throughput sequencing technology, and cellulars systems. The objective of the platform is from gene cloning to structure determination. It notably implemented an Illumina GAII sequencing Our mission is to provide researchers with state of the to accelerate the pace of discoveries by providing makes use of the following methods and cutting edge system. Since its installation, we have com- art high throughput technologies for analysing gene ex- technologies: pression and regulation. We provide array based applica- integrated high-throughput approaches to investi- pleted more than 50 projects and generated • Automated cloning (Gateway, SLIC, restriction, …) and tions such as Affymetrix microarrrays for gene expres- gate eukaryotic macromolecular complex systems mini-expression screening protocols using Tecan liquid over 3 terabases of sequences. Importantly, sion profiling, miRNA expression, SNP genotyping, and related to human health by using a continuum of handling systems. CNV analysis. We also provide Illumina high throughput our platform also provides support to resear- state-of-the-art technologies. These technologies • Protein production in various expression systems (bac- sequencing applications such as ChIP-seq, RNA-seq and chers for data analysis. Indeed, we have the teria, insect cells, mammalian cells). whole genome or targeted re-sequencing. range from gene cloning to structure determi- expertise (statistic and bioinformatic) and the • Parallel purification of proteins, nucleic acids and their nation and ultimately to cellular resolution. The complexes using Akta Xpress and Akta Purifier FPLC infrastructure (server and dedicated software) Full services involve all steps from quality checks of star- SBGP was registered by the RIO coordination in chromatographic systems. ting material, labelling and hybridisations for array appli- to conduct microarray and sequencing data 2003 and was confirmed in 2006 and 2008 by IBi- • Macromolecule characterization using different biophy- cations, library preparations and sequencing, and data sical methodologies (DLS, AUC, ITC). analysis. analysis. Support for in-depth bioinformatics and statis- SA. This national label implies that the platform • Automated crystallization of macromolecules using a Our platform is open to French and foreign tical data analysis for array and sequencing approaches is open to the scientific community and is impli- Cartesian nano-volume liquid handling robot. is also available. academic laboratories, and data obtained have cated in the important mission of training both • Structure elucidation on crystals (X-rays with Micromax contributed to numerous publications, many rotating anode from Rigaku) or in solution (EM, SAXS; scientists and technical staff within collaborative NMR). of them in the best international journals (82 So far, the platforms contributions have been published in ten articles.

107 Core facilities Core facilities

• Mass Spectrometry Facility •Transgenic Facility Adeline Page Andrée Dierich • Core service for Flow Cytometry The mass spectrometry facility provides the The Transgenic Facility generates mouse & Fluorescence-Activated IGBMC community with standard and dedicated models for in vivo gene function analysis by: Cell Sorting proteomic analyses for the characterization of • Classical transgenesis (micro-injection of Claudine Ebel proteins, including recent technological transgenes) This service allows investigators to perform developments. Among others, this includes pro- • Homologous recombination in mouse multi-parameter flow cytometry analysis and tein identification, protein modification detection embryonic stem cells. sorting of cells and particles in liquid and measurement of the molecular masses of • Tetraploid aggregation chimeras suspension based on size, granulosity and co- intact protein and non-covalent complexes. The lor of fluorescence. Two state-of-the-art analy- service is equipped with two ionic trap mass spec- • The Baculovirus Service zers (FACS, Calibur for 4 color analysis, LSR trometers (LTQ XL and LTQ Velos), an Isabelle Kolb-Cheynel and Nathalie Troffer-Charlier II for 15-color analysis) and two high-speed ESI-TOF mass spectrometer for analysis of The Baculovirus Expression Facility provides • Animal house sorters (FACSVantage SE option DIVA with molecular masses (MicrOTOF Focus) and a investigators with equipment, expertise and Head Animal House: Elisabeth Metzger 8 color capacity, FACSAria II with 15 color MALDI-TOF (Reflex IV) apparatus. custom services for protein production in insect Responsible Sanitary: Armelle Van Es capacity) are available to IGBMC scientists cells. Services include: generation, amplification The Animal House, which includes the and the Strasbourg scientific community. ICS, serves around 25 research groups at • Production of monoclonal & and maintenance of high-titer baculovirus stocks, The core service also provides protocols and polyclonal antibodies the IGBMC and accommodates approxi- analytical scale productions for protein-protein procedures for numerous applications. Mustapha Oulad-Abdelghani (monoclonal) mately 105,000 mice. Other than its animal interaction studies, optimization of protein Gilles Duval (polyclonal) maintenance roles and the technical assistance expression and preparative scale productions.< • Histopathology & Our service produces up to 40 monoclonal and granted to researchers, the animal house has Embryology Service 200 polyclonal antibodies per year for in-house specific activities such as the importation and Stéphanie Muller and external teams. The service can use recombi- exportation of animals, the rederivation and Mouse models are readily accessible to nant proteins or polypeptide coupled to ovalbu- the cryopreservation of mouse lines. post-mortem analyses at any time during mine for immunization of the mouse, rabbit or the course of a disease, including the stages • Cell Culture Facility rat. It also provides advice to design recombinant preceding its clinical onset. Thus, histological or synthetic antigens suitable to specific applica- Betty Heller analysis of mutant and/or treated mice tion. The facility maintains more than 2,000 cell provide a powerful means to draw on lines which include normal and tumoral cell pathophysiological scenarios. • Peptide synthesis lines from several origins. It produces 5,000 Pascal Eberling T-75 cm2 cell flasks, freezes 6,000 cryotubes, Peptide synthesis is performed on a 433A and prepares 5,000L of media per year. peptide synthesizer (ABI), using Fmoc chemistry. The facility also manages a L3 laboratory for Crude peptides are purified by inverse phase virus experiments. HPLC. End products are checked and characterized by HPLC and mass spectrometry.

109 Facts & figures Facts & figures

Statistics until June 30th A major part of IGBMC staff (62%) is located within lowing the pooling of resources: they represent 26% of research teams: these are statutary scientists, post-docs, our staff and work for both internal and external research A major part of IGBMC’s funding (87%) comes through INCA...) and/or European or International Programmes PhD students and technical staff. teams and/or industrial laboratories. The remaining 12% research grants. Our researchers apply to charities (AFM, (FP7, NIH, HFSP...). The other 13% comes from institu- Engineers and technicians with high levels of expertise cover administrative (Purchasing, Human Resources, Fi- FRM...), national public funding agencies (ANR, tional funding (CNRS-Inserm-Université de Strasbourg). are employed on our platforms and our core facilities al- nance...) , IT Service and Building Maintenance.

Research funding (except ICS) Staff allocations 3% 5% 13% 15% 12% Institutional funding 3% Public funding 12% Charities Research teams European Union funding IGBMC common 5% 18% International support Platforms Industrial contracts & licences Core Facilities Investments & services ICS 6% 62% 46%

Nationalities of staff scientists The IGBMC is an international center with48 different nationalities represented among its personnel. All activi- Distribution of statutary Distribution of staff scientists ties in the Institute are carried out in English. and non-statutary staff

32% 7% 17% 55% 768 employees (including ICS) 33% 13% 43 groups 12% 67% 33% 4 research programmes 5 platforms + ICS

31% France More than 200 publications/year EU (except France) 57 million Euros budget Non-Statutary staff Group leaders PhD students Others 14,000 m² of laboratories Statutary staff Staff scientists Master students Post-docs

111 staff scientists staff scientists Development & Stem Cells HEITZLER Pascal POURQUIE Olivier Functional Genomics & Cancer GRONEMEYER Hinrich METZGER/CHAMBON SERAPHIN Bertrand Integrated Structural Biology Coordinator : Genetic and molecular analysis Development of muscle and Coordinator: DAVIDSON Irwin From nuclear receptor action Genetic dissection of nuclear Protein networks and com- Coordinator : SCHULTZ Patrick LABOUESSE Michel of early neurogenesis in Droso- vertebrae Assistant: GASSERT Valerie to novel paradigms for cancer receptor signaling in the plexes regulating eukaryotic Assistant: NEY Anne Assistant: BRONNER Sylvianne phila melanogaster Scientists therapy action mouse mRNA decay Scientists KNOCKAERT Marie CHAN Susan/ KASTNER Philippe Scientists Scientists Scientists CAVARELLI Jean DOLLE Pascal HEITZLER Pascal POURQUIE Olivier Hematopoiesis and Leukemoge- GRONEMEYER Hinrich CHAMBON Pierre MAUXION Fabienne Structural biology of epigenetic Role of retinoic acid in mouse Postdoctoral fellows REBAGLIATI Michael nesis in the mouse Postdoctoral fellows KRUST Andrée SERAPHIN Bertrand targets development BIRYUKOVA Inna Postdoctoral fellows Scientists CESCHIN Danilo LI Mei Postdoctoral fellows Scientists Scientists Engineers/Technicians BENAZERAF Bertrand CHAN Susan KEDINGER Valérie METZGER Daniel DREUMONT Natacha CAVARELLI Jean BLOCH-ZUPAN Agnès ACKERMANN Claudine CADETE VILHAIS NETO Gonçalo KASTNER Philippe LUND Per Postdoctoral fellows GAS LOPEZ Maria CURA Vincent DOLLE Pascal Master Students CHAL Jérôme KIRSTETTER Peggy MENDOZA PARRA Marco HUA Guoqiang KOLESNIKOVA Olga ROMIER Christophe KREZEL Wojciech CHOONG Kee-Fong MARUHASHI Mitsuji Postdoctoral fellows Antonio JIANG Hua PhD Students WURTZ Jean-Marie RHINN Muriel SALLOUM Anastasia OGINUMA Masayuki CAI Qi PATTABHIRAMAN MUKHERJI Atish RISPAL Delphine Postdoctoral fellows Postdoctoral fellows SU Cheng Wen ORAVECZ Attila Shankara-Narayanan SURJIT Milan VAN DEN ELZEN Antonia HASSENBOEHLER Pierre PASCHAKI Marie JARRIAULT Sophie WAHL Matthias PhD Students PAVET-PORTAL Valeria PhD Students Engineers/Technicians MAREK Martin PhD Students In vivo analysis of cellular PhD Students APOSTOLOV Apostol PORTAL Maximiliano DUTEIL Delphine FAUX Céline PhD Students ETTER Guillaume plasticity in C. elegans ANTONI Bernadette KAVERI Deepika PhD Students GALI RAMAMOORTHY Thanuja GAUDON-PLESSE Claudine DIEBOLD Marie Laure KRZYZOSIAK Agnieszka Scientists BERA Agata LE LAY Anne-Solen KHANWALKAR Harshal GANTI Krishna Priya MULLER Benjamin LEPROULT Emeline LAUGEL Virginie JARRIAULT Sophie DE MOT Laurane MACIAS Beatriz Alejandra MUELLER Cathrin LEYVA CASTILLO Juan Manuel LIENHART Yann RATAJ Monika Postdoctoral fellows DENANS Nicolas MASTIO Jérôme VJETROVIC Jelena Engineers/Technicians SOUTOGLOU Evi MAILLIOT Justine Engineers/Technicians AHIER Arnaud KROL Aurélie Engineers/Technicians WALIA Mannu Kamalraj BORNERT Jean-Marc Cell Biology of genome Engineers/Technicians FRAULOB Valérie HAJDUSKOVA Martina Engineers/Technicians MARCHAL Patricia Engineers/Technicians FRIEDMANN Laetitia integrity TROFFER-CHARLIER Nathalie SCHUHBAUR Brigitte ZURYN Steven DALI Soraya Master Student ERB Cathie GARGOWITSCH Laëtitia Scientists Master Student PhD Students GARNIER Jean-Marie VESIN Rose-Marie LIEB Michèle HENER Pierre SOUTOGLOU Evi DEJAEGERE-STOTE Annick SCHUH Mélanie DANIELE Thomas KENNEDY Leif PAULI Cecilia HUC Magali Postdoctoral fellows Biocomputing Engineers/Technicians MONCUQUET Philippe DAVIDSON Irwin VALLET Judith MEYER Tania NAGY Zita Scientists GEORGES-LABOUESSE Elisabeth FISCHER Nadine PACE Jennifer Structure and function of the VAN GOOL Wouter Master Students PANKOTAI Tibor DEJAEGERE-STOTE Annick Integrin function and signaling in Master Students PLASSAT Jean-Luc general transcription factor TFIID YUJNOVSKY Irene BAGCI Hakan PhD Students STOTE Roland tissue morphogenesis, integrity Marie-Charlotte Morin TASSY Olivier Scientists Master Students TALEB Fatima HOFFBECK Anne-Sophie Postdoctoral fellows and homeostasis Master Student DAVIDSON Irwin BORIES Pierre LEMAITRE Charlène BROCHET Xavier Scientists LABOUESSE Michel GUENNOUN Rym MARTIANOV Igor WEISS Mélanie REINA SAN MARTIN Bernardo Engineers/Technicians SCHWARZ Benjamin DE ARCANGELIS Adèle Forces and signals in tissue MENGUS Gabrielle Molecular biology of B cells BONHOMME Céline PhD Students GEORGES-LABOUESSE Elisabeth morphogenesis RIVELINE Daniel Postdoctoral fellows HAMICHE A . Scientists FURST Audrey AMAL Ismail PhD Students Scientists Laboratory of Cell Physics ALPERN Daniil Chromatin and epigenetic REINA SAN MARTIN Bernardo FERRARIO Maria Giovanna TOSSE Lindzy GALLY Christelle Scientists KOBI Dominique regulation Postdoctoral fellows TORA Laszlo Engineers/Technicians LABOUESSE Michel RIVELINE Daniel LANGER Diana Scientists ROBERT Isabelle Chromatin modifications and KIEFFER Bruno PFISTER Véronique QUINTIN Sophie Engineers/Technicians PhD Students HAMICHE Ali ROTTNER Mathilde regulation of gene expression Biomolecular Nuclear Magnetic SIEBERT Stéphanie Postdoctoral fellows HOEL Antonin BENHADDOU Ataaillah RAMAIN Catherine PhD Students during differentiation Resonance KOLOTUEVA Irina CHOUKRALLAH Mohamed-Amin RAMAIN Philippe JEEVAN RAJ Beena Patricia Scientists Scientists GIANGRANDE Angela OSMANI Naël TORRES-PADILLA Maria Elena MOUTIER Emmanuel Postdoctoral fellows MILOSEVIC Sara DEVYS Didier DELSUC Marc-André Cellular and molecular ZHANG Huimin Epigenetics and cell fate in early STRUB Thomas DEPAUX Arnaud SCHIAVO Ebe TORA Laszlo KIEFFER Bruno mechanisms of nervous system PhD Students mammalian development Engineers/Technicians OUARARHNI Khalid Engineers/Technicians Postdoctoral fellows LEBARS Isabelle differentiation APAYDIN Ahmet Scientists MICHEL Isabelle PAPIN Christophe HEYER Vincent BALLARINO Monica Postdoctoral fellows Scientists Engineers/Technicians TORRES PADILLA Maria Elena YE Tao PhD Students Master Student FOURNIER Marjorie RAMIREZ RAMOS Juan Ramon GIANGRANDE Angela RODRIGUEZ David Postdoctoral fellows Master Student OBRI Arnaud OUBRAHAM Lila HELMRICH Anne QUINTERNET Marc Postdoctoral fellows Master Student BURTON Jonathan Adam URBAN Sylvia OURY Julien KARMODIYA Krishanpal PhD Students KOMONYI Orban PASTI Gabriella FADLOUN Anas SHUAIB Muhammad RIO Marie-Christine / UMLAUF David TANTY Matthieu LANEVE Pietro MIYANARI Yusuke EGLY Jean-Marc/COIN Frédéric TRIPATHI Vivek TOMASETTO Catherine PhD Students Engineers/Technicians POPKOVA Anna MARK Manuel/GHYSELINCK PhD Students Genome expression and repair YETTOU Guillaume Molecular and cellular biology BONNET Jacques LING Claude PhD Students Norbert SANTENARD Angèle Scientists Engineers/Technicians of breast cancer GYENIS Akos BERZSENYI Sara Retinoic acid signalling Engineers/Technicians COIN Frédéric DANIEL Dorothée Scientists KREBS Arnaud KLAHOLZ Bruno ERKOSAR Berra pathways driving stem sper- ZIEGLER-BIRLING Céline COMPE Emmanuel ALPY Fabien LANG Guillaume Large complexes involved in FLICI Hakima matogonia ontogenesis and Master Student EGLY Jean-Marc LOSSON R. DALI YOUCEF Nassim RISS Anne gene expression KARATAS Omer Faruk differentiation BENDER Ambre Postdoctoral fellows Scientists RIO Marie-Christine Engineers/Technicians Scientists KUMAR Arun Scientists EBEROVA Jitka CAMMAS Florence TOMASETTO Catherine SCHEER Elisabeth KLAHOLZ Bruno Engineers/Technicians GHYSELINCK Norbert VERMOT Julien HASHIMOTO Satoru Postdoctoral fellows Postdoctoral fellows STIERLE Matthieu OURJOUMTSEV Alexandre ARBOGAST Nadine MARK Manuel Mecano-genetic interplays and LE MAY Nicolas RICLET Raphaël BUACHE Emilie Postdoctoral fellows DIEBOLD Céline Postdoctoral fellows embryonic morphogenesis VELEZ-CRUZ Renier PhD Students PhD Students WASYLYK B. KRISHNAGIRI MURA Carole GELY PERNOT Aurore Scientists VITRENKO Yakov GRABER Céline DAGUENET Elisabeth Molecular and cellular biology VENKATASUBRAMANIAN Srividhya PAPALINI Giulia JACOBS Hugues VERMOT Julien PhD Students HERQUEL Benjamin LEGUEUX François of cancer MALETTA Massimiliano PhD Students Postdoctoral fellows GIRAUDON Christophe Engineers/Technicians ROUSSEAU Adrien Scientists MANICKA Sankar Narayanan GRADWOHL Gérard RAVERDEAU Mathilde GOETZ Jacky ILTIS Izarn CERVINO Margarita SIMOES David WASYLYK Bohdan MYASNIKOV Alexander Control of endocrine cells Engineers/Technicians MOJZISOVA Halina KORETS Roman LEROUGE Thierry TAN Jinxiang PhD Students ORLOV Igor differentiation in the pancreas DENNEFELD Christine PhD Students KRISTENSEN Hans-Ulrik Engineers/Technicians LI Yadong SIMONETTI Angelita and intestine FERET Betty HECKEL Emilie SINGH Amita STOLL Isabelle, technicienne SEMENCHENKO Kostyantyn PhD Students Scientists KLOPFENSTEIN Muriel Engineers/Technicians TRABOULSI Hussein WENDLING Corinne, ingénieur Engineers/Technicians TORCHY Morgan GRADWOHL Gérard Master Student GESCHIER Sandrine ZADORIN Anton WASYLYK Christine Engineers/Technicians MELLITZER Georg BOUROUINA Imane Rym ROTH Stéphane ZHOVMER Alexander ROCHETTE-EGLY Cécile HAZEMANN Isabelle Postdoctoral fellows Engineers/Technicians Nuclear retinoic acid receptors Attached researcher: MENETRET Jean-François BEUCHER Anthony VIVILLE Stéphane BRAUN Cathy phosphorylation and Cross- DU MANOIR Stanislas MERLE Carole Primordial germ cells’ ontogeny CATEZ Philippe talk with signaling pathways PhD Students Scientists LARNICOL Annabel Scientists NIVLET Laure KOSCINSKI Isabelle MARTEL Fernand EGLY Cécile PICCAND Julie TELETIN Marius PREVE Brigitte Postdoctoral fellows Engineers/Technicians VIVILLE Stéphane Master Student ALTANOUZY Ziad MEUNIER Aline Postdoctoral fellows ZIANI Salim DUONG Vanessa POULET Martine CELEBI Catherine PANKOTAI-BODO Gabriella Master Student EL RAMY GHOSN Rosy PhD Students STRASSER Perinne PhD Students FERRY Christine ELINATI Elias PISKUNOV Aleksandr JUNG Laura SAMARUT Eric Engineers/Technicians Engineers/Technicians ANDRE Cécile GAOUAR Samia SKORY Valérie LUTZING Régis TROPEL Philippe Master Students FOSSARD Camille TARABAY Yara

113 staff scientists & PLATFORMS Technical support & administration

MORAS Dino Translational medicine & REZAI Xavier PLATFORMS OULAD-ABDELGHANI ICS Phenotyping Management Purchasing / Stock Expression of genetic information Neurogenetics WEIBEL Raphaël Bioinformatics Mustapha, Antibodies Monoclonal SORG-GUSS Tania, Head of POURQUIE Olivier, MATHON Peggy Scientists Coordinator : KIEFFER Brigitte Engineers/Technicians PLEWNIAK Frédéric ANDRES Valérie Phenotyping Director of IGBMC CHARLES Christelle BILLAS-MASSOBRIO Isabelle Assistant: BRONNER Sylvianne ERBS Eric BIANCHETTI Laurent JUNG Nicole AMANN Grégory BENSEL Nicolas, FASSEL Serge DOCK-BREGEON Anne-Catherine FILLIOL Dominique GEOFFROY Véronique AUBURTIN Aurélie Director of Logistic & Scientific GERBER Philippe MORAS Dino CHARLET-BERGUERAND Nicolas KOEBEL Pascale RAFFELSBERGER Wolfgang DUVAL Gilles, Antibodies Polyclonal AUVRAY Sandy Operations KIENZLER Elise POTERSZMAN Arnaud Physiopathology of the RNA MATIFAS Audrey SIGUENZA Sophie MEMEDOV Djemalj BECHAKRA Malik LUNKES Astrid, MULLER Catherine ROCHEL-GUIBERTEAU Natacha gain-of-function diseases REISS David BECKER Julien Director of Scientific Affairs REINE Valérie RUFF Marc Scientists ROBE Anne Microarrays and Deep TROFFER-CHARLIER Nathalie, BEDU Elodie SCHAEFFER Katell, REPIS Christian Postdoctoral fellows CHARLET BERGUERAND Nicolas Sequencing Baculovirus BUNZ Isabel Director of Finance and SIGWALT Jessica ABDULRAHMAN Wassim Postdoctoral fellows KOENIG Michel THIBAULT-CARPENTIER Christelle KOLB-CHEYNEL Isabelle CES Aurélia Administration TAMAYO Sandrine ANTONY Pierre SELLIER Chantal Recessive ataxias ALUNNI Violaine VIALLE Chantal CHAMPY Marie-France WETZSTEIN Eric BRELIVET Yann PhD Students Scientists BAMBA Géraldine COMBE Roy Management Assistance LEVY Nicolas FREYERMUTH Fernande KOENIG Michel COLAS Ingrid HELLER Betty, DING Thomas BENARROCH Laurence Technical Department OSZ-PAPAI Judit RAU Frédérique Postdoctoral fellows DEMBELE Doulaye Cell culture & Cell Bank EL FERTAK Lahcen GONZALEZ Laetitia KOLB Claude, RADU Laura Engineers/Technicians ASSOUM Mirna HANAUER Antoine BOSSENMEYER Patricia FOUGEROLLE Jean-Victor KAUFFMANN Dominique Head of Technical Department TAKACS Maria FISCHER-HUMMEL Marie-Christine Engineers/Technicians HEROUARD-MOLINA Cathy CHRISTOFFEL Ghislaine GOETZ-REINER Patrice MEYER Estelle UNTEREINER Christophe, PhD Students FUGIER Charlotte DROUOT Nathalie JOST Bernard FELS Karine GUIMOND Alain SCHUBEL Françoise Deputy/Technical Department ALBOU Laurent Philippe HICKEL Pierre KEIME Céline FERANDEL Noëlle KOUTSEFF Alexis THORNTON Laura BEAUJEAN Frédéric MAILLOT Benoît LAPORTE Jocelyn LE GRAS Stéphanie MASTIO Leslie LALANNE Valérie KUNTZ Pascal MARTINEZ ZAPIEN Denise FABRE Jean-Etienne Mechanisms of neuromuscular VICAIRE Serge RIESTERER Hélène LE MARCHAND Elise Reception LANG Doris SCHAETZEL Aurélie Atherosclerosis and thrombosis disease SIGNOUR Aline LECOCQ Muriel ACKER Evelyne POIMBOEUF-MAHIEU Marc UCHIKAWA Emiko Scientists Scientists Structural Biology and Genomics LUX Aline MENNA Martine SCHERMULY Jean-Claude Engineers/Technicians FABRE Jean-Etienne LAPORTE Jocelyn Platform PAGE Adeline, MEZIANE Hamid TANTON Patrick EILER Sylvia Postdoctoral fellows Postdoctoral fellows BUSSO Didier Head of Mass spectrometry MITTELHAEUSER Christophe Human Ressources Department TAUBERT Serge PELUSO-ILTIS Carole BOUCHAREB-DAHOU Rihab COWLING Belinda BIRCK Catherine CHAVANT Virginie MONTIAL Marina PASQUIER Lydia, Head of VATTE Christophe SLIMANI Farid D’ALESSANDRO Manuela GRANGER Florence RUFFENACH Frank MOULAERT David Human Ressources VONSCHEIDT Régis POCH Olivier Engineers/Technicians HNIA Karim LITT Alain MULLER Stéphanie ACKER Dominique WEIL Luc Evolutionary systems biology TILLY Peggy KOUTSOPOULOS Olga MCEWEN Alastair EBEL Claudine, PETER Emilie FISCHER Joëlle Scientists ROYER ZEMMOUR Barbara POUSSIN-COURMONTAGNE Cell Sorting PETIT-DEMOULIERE Benoît LENTZ Brigitte House Maintenance POCH Olivier HANAUER André/ PhD Students Pierre PHAM THI BICH Hanh LESECQ Florence BINTEIN Cathy LECOMPTE Odile MANDEL Jean-Louis AMOASII Leonela SALIM Loubna EBERLING Pascal, POUILLY Laurent METAIS Bénédicte BORSCHNECK Denise MULLER Jean Mechanisms of monogenic TOSCH Valérie TROESCH Edouard Peptide synthesis RIET Fabrice PETILLON Armelle CRABEY Karine THOMPSON Julie forms of mental retardation ZIVKOVIC Ivana ROUSSEAU Stéphane ROTH Catherine EL YAMANI Hassan WICKER Nicolas Scientists Engineers/Technicians Imaging Center SUTTER-WOLTER Anne TOUSSAINT Elisabeth GREDLER Sylvie Postdoctoral fellows HANAUER André KOCH Catherine VONESCH Jean-Luc ICS TILLY Isabelle HAOUALA Ilias NGUYEN Ngoc Hoan MANDEL Jean-Louis KRETZ Christine HENTSCH Didier HERAULT Yann, ICS Director WAGNER Christel Communication HEITZ Nadine PhD Students MOINE Hervé SCHWAB Yannick SORG-GUSS Tania, Technical WEBER Bruno ESTEBAN-POURQUIE Silvia, LAACHARI Mohammed ANNO Yannick-Noël Postdoctoral fellows PUCCIO Hélène MESSADDEQ Nadia Director WENDLING Olivia Head of Communication PERAL Louisette ANIBA Mohamed Radhouane BOHM Johann Biology and Physiology of BOEGLIN Marcel BOUR Sandra PLANCHAT Catherine LINARD Benjamin PhD Students recessive ataxia DEISS Alexandre ICS Management Support ICS Mouse Facility LEGRAND Elodie SCHMITT Sylvie LUU Tien Dao MEHMOOD Tahir PUCCIO Hélène FAUNY Jean-Daniel BLONDELLE Eric GONCALVES DA CRUZ Isabelle, STIEFFEL Emma Engineers/Technicians SCHNEIDER Anne Postdoctoral fellows HERGUEUX Josiane CHEBBOUB Djaouida Veterinary Accounting/Controlling MOULINIER Luc TABET Ricardos BOYER Frédéric KESSLER Pascal FRICKER Bastien AYADI Abdelkader, Head of RAMOND Marie-Jeanne, POIDEVIN Laëtitia VASLI Nasim MARTELLI Alain KOCH Marc NAGRE Isabelle Animal Facility Department Head of Finance RIPP Raymond Engineers/Technicians TESCHNER Julia LUTZ Yves PENSAVALLE Joëlle ALI-HADJI Dalila PINCHON Frédérique, PANNETIER Solange WATTENHOFER-DONZE Marie SPIEGELHALTER Coralie RIO-ZENNER Fanny ANDRE Philippe Head of Controlling SCHULTZ Patrick FLATTER Eric PhD Students WEICKERT Jean-Luc SELLOUM Mohammed BAM’HAMED Chaouki HOFFER Stéphane Architecture of HAUMESSER Nicolas COLIN Florent BANQUART-OTT Nadine Head of Accounting Nucleoprotein Systems by 3-D LICITRA Floriana High Throughput Cell-based ICS Bioinformatics BOUR Raphaël CARBONNIER Laëtitia Electron Microscopy HERAULT Yann SCHMUCKER Stéphane Screening Platform VASSEUR Laurent, BRIGNON Sophie GAUPP Cindy Scientists Physiopathology of aneuploidy, Engineers/Technicians BRINO Laurent Head of Bioinformatics CHARLES Philippe GONTHIER Patricia DRILLIEN Robert gene dosage effect and Down REUTENAUER Laurence FISCHER Benoit DEBOUZY Guillaume DELANGLE Benoît GRUFFAZ Agnès LAMOUR Valérie syndrome VAUCAMPS Nadège FROIDEVAUX Laure LEBLANC Sophie EL FERTAK Leila HECKER Annick SCHULTZ Patrick Scientists Master MOUNE-DIMALA Martin MORO Anne-Isabelle ENNAH Hamid MUNIER Brigitte Postdoctoral fellows BRAULT Véronique HICK Aurore WEISS Amélie FISCHER Fabienne RACK Nicole PAPAI Gabor HERAULT Yann ICS Genetic Engineering and FISCHER Natacha REGNERY Véronique PRADEAU AUBRETON Karine Postdoctoral fellows TROTTIER Yvon Model Validation GRUBER Frédéric UFFLER Sylvie PhD Students MARECHAL Damien Pathogenic mechanisms of Cores Facilities PAVLOVIC Guillaume, Head HEMMERLE Mathieu KIZILYAPRAK Caroline RAVEAU Matthieu polyglutamine expansion diseases VAN ES Armelle, of Mutagenesis, Transgenesis KUJATH Christelle Valorisation/Grant PAPILLON Julie SALEH Abdelsalam Scientists Veterinary & Molecular Phenotyping KURTZ Caroline Management Engineers/Technicians Engineers/Technicians MERIENNE Karine METZGER Elisabeth, Department LANTZ-CHAMPY Charlotte BROOKS Steve CRUCIFIX Corinne CHEVALIER Claire TROTTIER Yvon Head of Animal House AUGE Fabrice LAEUFER Laurent DAUZET Frédéric DURAND Alexandre DUCHON Arnaud Postdoctoral fellows BLONDELLE Asmae BIRLING Marie-Christine LEGEAY Sandrine RUHLMANN Christine NALESSO Valérie KLEIN Fabrice CHRIST Lydia CARADEC Claudia MELLUL Peggy Systems Architect/Administrator SIMONI Albin PhD Students DELAPORTE Claude CAYROU Pauline MOKNI Mourad MOUTAUX Tony SPEHNER Danièle KIEFFER Brigitte DAVRANCHE Aurélien DIETRICH Holly CHARTOIRE Nathalie OHLMANN Thierry OFFNER Michel The opioid system and brain GOULA Agathi-Vasiliki DUFOUR Stephane DIERICH Andrée SCHMITT Raphaël YUSUPOV Marat function KARAM Alice EISENMANN Aurélie DREYER Dominique SCHOEDEL Christophe IT Service Ribosomes Scientists Engineers/Technicians FALCONE Sylvie EGLINGER Yolande SEILER Stéphane FRITZ Rémy, Head of IT Service Scientists BECKER Jérôme WEBER Chantal GENDRON Michaël ERBS Valérie TOUBARI Chadia MALLOUH Véronique JENNER Lasse Bohl BEFORT Katia Master HACHEM Rabiaa ESSABRI Karim UZUN Ibrahim CERDAN Stéphane YUSUPOV Marat GAVERIAUX-RUFF Claire EL KHOURY Rita HIRLIMANN Anne-Lise HELMSTETTER-VERDOT Cindy VINCENT Cindy RONGVAUX Youry YUSUPOVA Gulnara KIEFFER Brigitte JAWAD Agouna JACQUOT Sylvie WALCH Laëtitia SEITH Guillaume Postdoctoral fellows MASSOTTE Dominique KHADRAOUI Hafid KLEISS Charlotte WETZSTEIN Eric TOUSSAINT Jean-Luc BEN SHEM Adam OUAGAZZAL Abdel-Mouttalib KORCHI Hafid LINDNER Loïc WIECROCK Cyrille UGE Serge DEMESHKINA Natalia ROUX Michel KORCHI Nordine LORENTZ Romain WIECROCK Ludovic VERLEY Philippe MELNIKOV Sergey STEPHAN Aline MAGNANT William LUPPI Laurence ZANINELLO Fabienne ZOUIOUIECH Agathe PhD Students Postdoctoral fellows MEMEDOV Fatima MERTZ Annelyse ZANINELLO Nathalie GARREAU DE LOUBRESSE Nicolas DARCQ Emmanuel POIROT Martine QUEUCHE Danielle Hygiene Safety Engineers/Technicians LE MERRER Julie RICHERT Mourad ROTH Christelle BIELLMANN Dominique DUCLAUD Sylvie NOZAKI TAKAHASHI Chihiro SIEGEL Sabine ROUSSEAU Valérie PETERSCHMITT Yvan VINCENT Alexandre SCHWOERER Marie-Jeanne Library Attached Scientists: SEBAI Sarra ZINK Nicolas SEITZ Thierry MARTINA Hélène PODJARNY Alberto PhD Students VENTEO Lydie PENEY Marie-Thérèse COUSIDO-SIAH Alexandra CHU SIN CHUNG Paul WALLERICH Sandrine MITSCHLER André DEL BOCA Carolina DENIZ Sercan FAGET Lauren GARDON Olivier LUTZ Pierre-Eric

115 prizes & distinctions publications Until June 2010

2010, Pediatric Pathology Research 2008, CNRS Bronze Medal, 2004, IPSEN Neuronal Plasticity, Amsen E, Alfred J, Pourquie O (2010) Börjesson A, Lagerquist M, Liu C, Shao R, Costello P, Nicolas R, Willoughby J, Wasy- Fourcade S, Ruiz M, Guilera C, Hahnen The Node: a place to discuss, debate Windahl S, Karlsson C, Sjögren K, Mové- lyk B, Nordheim A, Treisman R. J Immunol. E, Brichta L, Naudi A, Portero-Otin M, Senior Prize 2009, Bruno KLAHOLZ Jean-Louis MANDEL and deliberate developmental biology. rare-Skrtic S, Antal M, Krust A, Mohan S, 2010 Jun 16. [Epub ahead of print]PMID: Dacremont G, Cartier N, Wanders R, Jocelyn LAPORTE 2004, Ipsen Endocrine Development 137: 2251 Chambon P, Sävendahl L, Ohlsson C. The 20554967 [PubMed - as supplied by Kemp S, Mandel JL, Wirth B, Pamplona role of estrogen receptor-alpha in growth Publisher] Ternary Complex Factors SAP-1 R, Aubourg P, Pujol A (2010) Valproic acid 2008 Nominated Inventor of communication and regulation, Anheim M, Fleury M, Monga B, Laugel V, plate cartilage for longitudinal bone growth. and Elk-1, but Not Net, Are Functionally induces antioxidant effects in X-linked 2010, Fondation Gairdner Prize the Year by the European Patent Pierre CHAMBON Chaigne D, Rodier G, Ginglinger E, Boulay J Bone Miner Res. 2010 Jun 18. Equivalent in Thymocyte Development. adrenoleukodystrophy. Hum Mol Genet C, Courtois S, Drouot N, Fritsch M, De- 19: 2005-14 (Canada), Pierre CHAMBON Office,Bertrand SÉRAPHIN launoy JP, Stoppa-Lyonnet D, Tranchant C, Bossenmeyer-Pourie, C., S. Blaise, G. Pou- Cronin T, Raffelsberger W, Lee-Rivera I, 2004, Grand Prix INSERM 2004, Koenig M (2010) Epidemiological, clinical, rie, C. Tomasetto, S. Audonnet, S. Ortiou, V. Jaillard C, Niepon ML, Kinzel B, Clerin E, Friedrich A, Garnier N, Gagniere N, paraclinical and molecular study of a cohort Koziel, M. C. Rio, J. L. Daval, J. L. Gueant, Petrosian A, Picaud S, Poch O, Sahel JA, Nguyen H, Albou LP, Biancalana V, Bettler 2010, Eurosystem Young 2007, Madeleine Lecoq Prize, Jean-Marc EGLY of 102 patients affected with autosomal and B. Beck, 2010, Methyl donor deficiency Leveillard T (2010) The disruption of the E, Deleage G, Lecompte O, Muller J, Investigator Award, Académie des Sciences, recessive progressive cerebellar ataxia affects fetal programming of gastric ghrelin rod-derived cone viability gene leads to Moras D, Mandel JL, Toursel T, Moulinier Sophie JARRIAULT Julie THOMPSON-MAALOUM 2004, ESHG Young Scientist from Alsace, Eastern France: implications cell organization and function in the rat: Am photoreceptor dysfunction and suscepti- L, Poch O (2010) SM2PH-db: an interactive for clinical management. Neurogenetics J Pathol, v. 176, p. 270-7. bility to oxidative stress. Cell Death Differ system for the integrated analysis of Award, Aurora PUJOL 11: 1-12 17: 1199-210 phenotypic consequences of missense 2009, Ligue Contre le Cancer 2007, Jules Martin Prize, Académie Boumlic A, Nomine Y, Charbonnier S, mutations in proteins involved in human Antony P, Sigueiro R, Huet T, Sato Y, Dalagiorgou G, Vassilaki N, Kieffer B, Trave Degletagne C, Keime C, Rey B, de Dine- genetic diseases. Hum Mutat 31: 127-35 René et Andrée Duquesne Prize, des Sciences, Daniel METZGER 2004, Edwin B. Astwood Award, Ramalanjaona N, Rodrigues LC, Mourino G, Mavromara P, Orfanoudakis G (2010) chin M, Forcheron F, Chuchana P, Jouventin Jean-Marc EGLY Paolo SASSONE-CORSI A, Moras D, Rochel N (2010) Structure- Prevalence of intrinsic disorder in the P, Gautier C, Duchamp C. 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J lating the function of the serine/arginine-rich Chambon P, Hardman MJ, Ashcroft GS cell-based reporter gene assays using Immunol. 2010 Jun 16. proteins 9G8 and Tra2-{beta}: J Cell Sci, v. (2010) 17Beta-estradiol inhibits wound THOMPSON-MAALOUM droplet-based microfluidics. Chem Biol 123, p. 40-50. healing in male mice via estrogen receptor- 2009, Académie Nationale de 17: 528-36 Canto C, Jiang LQ, Deshmukh AS, alpha. Am J Pathol 176: 2707-21 Mataki C, Coste A, Lagouge M, Zierath Dreumont N, Hardy S, Behm-Ansmant Médecine Prize, 2005, Helmholtz Humboldt Re- Ben Khedher S, Zouari N, Messaddeq JR, Auwerx J (2010) Interdependence of I, Kister L, Branlant C, Stevenin J, Bour- Guilini C, Urayama K, Turkeri G, Dedeoglu Jean-Louis MANDEL search Prize, Laszlo TORA N, Schultz P, Jaoua S. 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Mutations in Lama1 disrupt stress in skeletal muscle stimulates early 2009, Gutenberg Prize, 2005, Grand Prix Ruban Rose de la R (2010) Detection of nucleic acid-nuclear retinal vascular development and inner expression of Rad in a mouse model of Bruno KLAHOLZ Recherche, Marie-Christine RIO hormone receptor complexes with mass Cheng L, Guo J, Sun L, Fu J, Barnes PF, limiting membrane formation. J Biol Chem. amyotrophic lateral sclerosis. Free Radic spectrometry. J Am Soc Mass Spectrom Metzger D, Chambon P, Oshima RG, 2010 Mar 5;285(10):7697-711. Biol Med. 2010 Apr 1;48(7):915-23. Epub 21: 635-45 Amagai T, Su DM (2010) Postnatal Tissue- 2010 Jan 14.PMID: 20079427 [PubMed in 2008, Fondation pour la Recherche 2004, Richard Lounsbery, Acadé- specific Disruption of Transcription Factor Fabre, J. E., and M. E. Gurney, 2010, process]Related citations Médicale Comité Alsace Scientific mie des Sciences, France et USA Bieniossek C, Nie Y, Frey D, Olieric FoxN1 Triggers Acute Thymic Atrophy. J Biol Limitations of current therapies to prevent N, Schaffitzel C, Collinson I,Romier Chem 285: 5836-47 thrombosis: a need for novel strategies: Heitzler P. (2010) Biodiversity and noncano- Prize, Sophie JARRIAULT Brigitte KIEFFER C, Berger P, Richmond TJ, Steinmetz Mol Biosyst, v. 6, p. 305-15. nical Notch signaling. In «Notch signaling». MO, Berger I. Automated unrestricted Claeys KG, Maisonobe T, Bohm J, Laporte CTDB 92, 427-451 (R. Kopan, Ed). Elsevier multigenerecombineering for multiprotein J, Hezode M, Romero NB, Brochier G, Facca S, Cortez C, Mendoza-Palomares Inc., San Diego. 2008, Prix Jean et Madeleine 2004, Prix Harland Winfield complex production. Nat Methods. 2009 Bitoun M, Carlier RY, Stojkovic T (2010) C, Messadeq N, Dierich A, Johnston AP, Schaeverbeke de la Fondation de Mossman en Biologie du Dévelop- Jun;6(6):447-50. 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J Proteome Res 9: 2496-507 2010 May 23. self-administering cocaine regulates lissencephaly gene-1 and reelin gene Sciences, Frédéric COIN Catherine TOMASETTO expression, as revealed by microarray technique. J Neurochem 113: 236-47

117 publications Until June 2010 publications Until June 2010

Hussenet T, Dali S, Exinger J, Monga B, Klink A, Lancelot E, Ballet S, Vucic E, Marcais A, Jeannet R, Hernandez L, Sou- Muller J, Stoetzel C, Vincent MC, Leitch Petit-Haertlein I, Blakeley MP, Howard E, Ha- Sharif T, Auger C, Alhosin M, Ebel C, Achour Walter A, Etienne-Selloum N, Brasse D, Jost B, Dembelé D, Martinet N, Thibault Fabre JE, Gonzalez W, Medina C, Corot lier J, Sigaux F, Chan S, Kastner P (2010) CC, Laurier V, Danse JM, Helle S, Marion V, zemann I, Mitschler A, Podjarny A, Haertlein M, Etienne-Selloum N, Fuhrmann G, Bronner Khallouf H, Bronner C, Rio MC, Beretz A, C, Huelsken J, Brambilla E, du Manoir S. C, Mulder WJ, Mallat Z, Fayad ZA (2010) Genetic inactivation of Ikaros is a rare event Bennouna-Greene V, Vicaire S, Megarbane M (2010) Incorporation of methyl-protonated C, Schini-Kerth VB (2010) Red wine polyphe- Schini-Kerth VB. Intake of grape-derived SOX2 is an oncogene activated by recur- Magnetic resonance molecular imaging in human T-ALL. Leuk Res 34: 426-429 A, Kaplan J, Drouin-Garraud V, Hamdani M, valine and leucine residues into deuterated nols cause growth inhibition and apoptosis polyphenols reduces C26 tumor growth by in- rent 3q26.3 amplifications in human lung of thrombosis in an arachidonic Acid Sigaudy S, Francannet C, Roume J, Bitoun ocean pout type III antifreeze protein: expres- in acute lymphoblastic leukaemia cells by hibiting angiogenesis and inducing apoptosis. squamous cell carcinomas. PLoS One. mouse model using an activated platelet Marchetti G, Escuin S, van der Flier A, P, Goldenberg A, Philip N, Odent S, Green sion, crystallization and preliminary neutron inducing a redox-sensitive up-regulation of p73 FASEB J. 2010, In press 2010 Jan 29;5(1):e8960. targeted probe. Arterioscler Thromb Vasc De Arcangelis A, Hynes RO, Georges- J, Cossee M, Davis EE, Katsanis N, Bon- diffraction studies. Acta Crystallogr Sect F and down-regulation of UHRF1. Eur J Cancer Biol 30: 403-10 Labouesse E (2010) Integrin alpha5beta1 is neau D, Verloes A, Poch O, Mandel JL, Struct Biol Cryst Commun 66: 665-9 46: 983-94 Warther D, Bolze F, Leonard J, Gug S, Specht Hussenet, T., D. Dembele, N. Martinet, J. necessary for regulation of radial migration Dollfus H (2010) Identification of 28 novel A, Puliti D, Sun XH, Kessler P, Lutz Y, M. Vignaud, and S. du Manoir, 2010, An Kobi D, Steunou AL, Dembele D, Legras of cortical neurons during mouse brain mutations in the Bardet-Biedl syndrome Pradeau-Aubreton K, Ruff M, Garnier Shimura E, Hozumi N, Kanagawa O, Metzger Vonesch JL, Winsor B, Nicoud JF, Goeldner adult tissue-specific stem cell molecular S, Larue L, Nieto L, Davidson I (2010) development. Eur J Neurosci 31: 399-409 genes: the burden of private mutations in JM, Schultz P, Drillien R. (2010) Vectors for D, Chambon P, Radtke F, Hirose S, Nakano M (2010) Live-Cell One- and Two-Photon phenotype is activated in epithelial cancer Genome-wide analysis of POU3F2/BRN2 an extensively heterogeneous disease. recombinational cloning and gene expression N (2010) Epidermal gammadelta T cells Uncaging of a Far-Red Emitting Acridinone stem cells and correlated to patient promoter occupancy in human melanoma Marsaud V, Tchakarska G, Andrieux G, Liu Hum Genet 127: 583-93 in mammalian cells using modified vaccinia sense precancerous cellular dysregulation Fluorophore. J Am Chem Soc 132: 2585-2590 outcome: Cell Cycle, v. 9, p. 321-7. cells reveals Kitl as a novel regulated JM, Dembele D, Jost B, Wdzieczak-Bakala virus Ankara. Anal Biochem. 404, 103-105 and initiate immune responses. Int Immunol target gene. Pigment Cell Melanoma Res J, Renoir JM, Sola B (2010) Cyclin K and Muller-Steffner H, Kuhn I, Argentini M, 22: 329-40 Wasylyk C, Zambrano A, Zhao C, Brants Jenner LB, Demeshkina N, Yusupova 23: 404-18 cyclin D1b are oncogenic in myeloma cells. Schuber F (2010) Identification of the N- Procter JB, Thompson J, Letunic I, Creevey J, Abecassis J, Schalken JA, Rogatsch H, G, Yusupov M (2010) Structural aspects Mol Cancer 9: 103 glycosylation sites on recombinant bovine C, Jossinet F, Barton GJ (2010) Visualization of Soyer, J., L. Flasse, W. Raffelsberger, A. Schaefer G, Pycha A, Klocker H, Wasylyk B. of messenger RNA reading frame Koch M, Diebold ML, Cavarelli J, Romier CD38 expressed in Pichia pastoris: their multiple alignments, phylogenies and gene Beucher, C. Orvain, B. Peers, P. Ravassard, Int J Cancer. 2010 Feb 16. [Epub ahead of maintenance by the ribosome. Nat Struct C (2010) Crystallization and preliminary Marty C, Lacout C, Martin A, Hasan S, Jac- impact on enzyme stability and catalytic family evolution. Nat Methods 7: S16-25 J. Vermot, M. L. Voz, G. Mellitzer, and G. print]PMID: 20162578 [PubMed - as supplied Mol Biol 17: 555-60 crystallographic analysis of eukaryotic quot S, Birling MC, Vainchenker W, Villeval. activity. Protein Expr Purif 70: 151-7 Gradwohl, 2010, Rfx6 is an Ngn3-dependent by publisher] Tubulin tyrosine ligase like 12, link transcription and mRNA export factor Myeloproliferative neoplasm induced by Qiu, J. J., X. Lu, B. B. Zeisig, Z. Ma, X. Cai, S. winged helix transcription factor required for to prostate cancer through tubulin post-trans- Jimenez-Lara, A. M., A. Aranda, and Iws1 from Encephalitozoon cuniculi. constitutive expression of JAK2V617F in Nagy, Z., A. Riss, S. Fujiyama, A. Krebs, Chen, H. Gronemeyer, D. J. Tweardy, C. W. pancreatic islet cell development: Develop- lational modification and chromosome ploidy. H. Gronemeyer, 2010, Retinoic acid Acta Crystallogr Sect F Struct Biol Cryst knock-in mice. M. Orpinell, P. Jansen, A. Cohen, H. G. So, and S. Dong, 2010, Leukemic transfor- ment, v. 137, p. 203-12. protects human breast cancer cells against Commun 66: 207-10 Stunnenberg, S. Kato, and L. Tora, 2010, mation by the APL fusion protein PRKAR1A- Wicker N (2010) Perfect sampling algorithm etoposide-induced apoptosis by NF- Mavrakis M, Pourquie O, Lecuit T (2010) The metazoan ATAC and SAGA coactivator RAR{alpha} critically depends on recruitment of Spiegelhalter C, Tosch V, Hentsch D, Koch for small mxn contingency tables. STATISTICS kappaB-dependent but cIAP2-independent Kolotuev, I., Y. Schwab, and M. Lighting up developmental mechanisms: HAT complexes regulate different sets of RXR{alpha}: Blood, v. 115, p. 643-52. M, Kessler P, Schwab Y, Laporte J (2010) AND COMPUTING 20: 57-61 mechanisms: Mol Cancer, v. 9, p. 15. Labouesse, 2010, A precise and rapid how fluorescence imaging heralded a new inducible target genes: Cell Mol Life Sci, v. From Dynamic Live Cell Imaging to 3D mapping protocol for correlative light and era. Development 137: 373-87 67, p. 611-28. Reichman, S., R. K. Kalathur, S. Lambard, Ultrastructure: Novel Integrated Methods for Wilhelm E, Kornete M, Targat B, Vigneault- Joseph A, Hess RA, Schaeffer DJ, Ko C, electron microscopy of small invertebrate N. Ait-Ali, Y. Yang, A. Lardenois, R. Ripp, O. High Pressure Freezing and Correlative Light- Edwards J, Frontini M, Tora L, Benecke A, Bell Hudgin-Spivey S, Chambon P, Shur BD organisms: Biol Cell, v. 102, p. 121-32. McClelland V, Cullup T, Bodi I, Ruddy D, Buj- Nakade K., Wasylyk B., Yokoyama K.K. Poch, D. J. Zack, J. A. Sahel, and T. Leveillard, Electron Microscopy. PLoS One 5: e9014 B (2010) TAF6delta orchestrates an apoptotic (2010) Absence of estrogen receptor alpha Bello A, Biancalana V, Boehm J, Bitoun (2010) Epigenetic regulation of p16Ink4a and 2010, The homeobox gene CHX10/VSX2 transcriptome profile and interacts functionally leads to physiological alterations in the Krebs A. R., Demmers J., Karmodiya M, Miller O, Jan W, Menson E, Amaya Arf by JDP2 in cellular senescence regulates RdCVF promoter activity in the inner Tora L, Timmers HT (2010) The TATA box regu- with p53. BMC Mol Biol 11: 10 mouse epididymis and consequent defects K., Chang N.C., Chang A.C. and Tora L. L, Trounce J, Laporte J, Mohammed S, retina: Hum Mol Genet, v. 19, p. 250-61. lates TATA-binding protein (TBP) dynamics in in sperm function. Biol Reprod 82: 948-57 (2010) ATAC and Mediator coactivators Sewry C, Raiman J, Jungbluth H (2010) Vici Niculescu C, Ganduli-Indra G, Pfister vivo. 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123 publications 2009 Notes

Vlastos, F., S. Lacomme, P. Wild, S. Poulain, J. Siat, G. Grosdidier, S. du Manoir, B. Monga, G. Hillas, R. Varsovie, F. Claudot, B. Marie, J. M. Vignaud, and N. Szymanski, 2009, Do evolving practices improve survival in operated lung cancer patients? A biobank may answer: J Thorac Oncol, v. 4, p. 505-11.

Volle, D. H., M. Decourteix, E. Garo, J. McNeilly, P. Fenichel, J. Auwerx, A. S. McNeilly, K. Schoonjans, and M. Benah- med, 2009, The orphan nuclear receptor small heterodimer partner mediates male infertility induced by diethylstilbestrol in mice: J Clin Invest, v. 119, p. 3752-64.

Wang, X., C. G. Sansam, C. S. Thom, D. Metzger, J. A. Evans, P. T. Nguyen, and C. W. Roberts, 2009, Oncogenesis caused by loss of the SNF5 tumor suppressor is dependent on activity of BRG1, the ATPase of the SWI/SNF chromatin remodeling complex: Cancer Res, v. 69, p. 8094-101.

Wendling, O., J. M. Bornert, P. Chambon, and D. Metzger, 2009, Efficient temporally- controlled targeted mutagenesis in smooth muscle cells of the adult mouse: Genesis, v. 47, p. 14-18.

Williams, J. A., N. Kondo, T. Okabe, N. Takeshita, D. M. Pilchak, E. Koyama, T. Ochiai, D. Jensen, M. L. Chu, M. A. Kane, J. L. Napoli, M. Enomoto-Iwamoto, N. Ghyselinck, P. Chambon, M. Pacifici, and M. Iwamoto, 2009, Retinoic acid receptors are required for skeletal growth, matrix homeostasis and growth plate function in postnatal mouse: Dev Biol, v. 328, p. 315-27.

Wolf, A. I., D. Buehler, S. E. Hensley, L. L. Cavanagh, E. J. Wherry, P. Kastner, S. Chan, and W. Weninger, 2009, Plas- macytoid dendritic cells are dispensable during primary influenza virus infection: J Immunol, v. 182, p. 871-9.

Wu, C., F. Ivars, P. Anderson, R. Hallmann, D. Vestweber, P. Nilsson, H. Robenek, K. Tryggvason, J. Song, E. Korpos, K. Loser, S. Beissert, E. Georges-Labouesse, and L. M. Sorokin, 2009, Endothelial basement membrane laminin alpha5 selectively inhibits T lymphocyte extravasation into the brain: Nat Med, v. 15, p. 519-27.

Yu, J., and J. Auwerx, 2009, The role of sirtuins in the control of metabolic homeostasis: Ann N Y Acad Sci, v. 1173 Suppl 1, p. E10-9.

Zeitlin SG, Baker NM, Chapados BR, Sou- toglou E, Wang JY, Berns MW, Cleveland DW. Double-strand DNA breaks recruit the centromeric histone CENP-A.

Zhang, Z., P. Hener, N. Frossard, S. Kato, D. Metzger, M. Li, and P. Chambon, 2009, Thymic stromal lymphopoietin overproduced by keratinocytes in mouse skin aggravates experimental asthma: Proc Natl Acad Sci U S A, v. 106, p. 1536-41.

Zhao, Z., C. Park, M. A. McDevitt, C. Glidewell-Kenney, P. Chambon, J. Weiss, J. L. Jameson, and J. E. Levine, 2009, p21-Activated kinase mediates rapid estradiol-negative feedback actions in the reproductive axis: Proc Natl Acad Sci U S A, v. 106, p. 7221-6.

Ziegler-Birling, C., A. Helmrich, L. Tora, and M. E. Torres-Padilla, 2009, Distribution of p53 binding protein 1 (53BP1) and phosphorylated H2A.X during mouse preimplantation development in the absence of DNA damage: Int J Dev Biol, v. 53, p. 1003-11.

Zsindely, N., T. Pankotai, Z. Ujfaludi, D. Lakatos, O. Komonyi, L. Bodai, L. Tora, and I. M. Boros, 2009, The loss of histone H3 lysine 9 acetylation due to dSAGA- specific dAda2b mutation influences the expression of only a small subset of genes: Nucleic Acids Res, v. 37, p. 6665-80.

125 NOTES Notes

127 where we are

A35 PARIS NANCY METZ STRASBOURG

route de Colmar Highway exit N°5 Illkirch-Nord STRASBOURG Baggersee Tram A Direction Illkirch CITY CENTER Lixenbuhl

Hypermarket

N Direction

Parc d’Innovation N NE

NW E

W SE SW O S

e S

A35 A

l f r e

MULHOUSE d

COLMAR K

Aéroport s

t Strabourg-Enztheim l e

r Highway exit N°5 Faculté de Illkirch-Graenstaden Pharmacie Strasbourg-Meinau

Tram A Station Campus Illkirch

Tram A Pôle API Direction Hautepierre Bld Sébastien Maillon Brandt

Parc d’Innovation

From Strasbourg airport (Entzheim): Or walking: Take the shuttle (train, TER every 15 mins) that stops at Cross the tracks and passing by the Velo Parc, continue the Strasbourg railway station: Journey time is 10 minutes. on to the roundabout. Take Boulevard Sebastien Brant © Copyright 2010 From Strasbourg railway station: (third exit). At the second roundabout take the first exit, Produced by: Underground trams leave every 5 minutes. Take Tram A Boulevard Gonthier d’Andernach and turn left in to Rue IGBMC (direction Illkirch Lixenbuhl). Alight at the stop Campus Laurent Fries. The IGBMC will be on your right. Texts: IGBMC Teams, Technical Platforms, Core Facilities, Students & Post-docs Board d’Illkirch. Journey time is 25 minutes. Print: By car: Valblor From the Tram station Campus d’Illkirch: Take the 5th Highway exit and then follow the direction Conception, Design, and Layout: Take the Bus 63 (direction Plobsheim Rhin) and alight Parc d’innovation. At the first roundabout take the fourth Office of Communication IGBMC, at the stop Parc d’Innovation. Follow Boulevard Sebastien exit, Boulevard Sebastien Brant, then at the second take Photography: Brant. At the roundabout, follow the second exit, Boule- the second exit and turn left in to Rue Laurent Fries. The Lola Velasquez, Patrice Latron, vard Gonthier d’Andernach and turn left on to Rue Lau- IGBMC will be on your right. Office of Communication IGBMC rent Fries. The IGBMC will be on your right. A big thank you goes out to all !

Institut de Génétique et de Biologie Moléculaire et Cellulaire 1 rue Laurent Fries / 67404 Illkirch CEDEX / France [email protected]