the center for integrative genomics report 07-08

www.unil.ch/cig Table of Contents introduction 2 The CIG at a glance 2 The CIG Scientific Advisory Committee 3 Message from the Director 4

Research 6 Richard Benton Chemosensory perception in Drosophila: from genes to behaviour 8 Béatrice Desvergne Networking activity of PPARs during development and in adult metabolic homeostasis 10 Christian Fankhauser The effects of light on plant growth and development 12 Paul Franken Genetics and energetics of sleep homeostasis and circadian rhythms 14 Nouria Hernandez Mechanisms of basal and regulated RNA polymerase II and III transcription of ncRNA in mammalian cells 16 Winship Herr Regulation of cell proliferation 18 Henrik Kaessmann Mammalian evolutionary genomics 20 Sophie Martin Molecular mechanisms of cell polarization 22 Liliane Michalik Transcriptional control of tissue repair and angiogenesis 24 Alexandre Reymond Genome structure and expression 26 Andrzej Stasiak Functional transitions of DNA structure 28 Mehdi Tafti Genetics of sleep and the sleep EEG 30 Bernard Thorens Molecular and physiological analysis of energy homeostasis in health and disease 32 Walter Wahli The multifaceted roles of PPARs 34 Other groups at the Génopode 37

Core facilities 40 Lausanne DNA Array Facility (DAFL) 42 Protein Analysis Facility (PAF) 44 Core facilities associated with the CIG 46

Education 48 Courses and lectures given by CIG members 50 Doing a PhD at the CIG 52 Seminars and symposia 54 The CIG annual retreat 62 The CIG and the public 63 Artist in residence at the CIG 63

PeoplE 64

1 Introduction

The Center for Integrative Genomics (CIG) at a glance

The Center for Integrative Genomics (CIG) is the newest depart- ment of the Faculty of Biology and Medicine of the University of Lausanne (UNIL). Its establishment was made possible as a result of the program “Sciences, Vie, Société”, a tri-institutional program linking the Universities of Geneva and Lausanne and the Federal Institute of Technology in Lausanne (Ecole polytechnique fédérale de Lausanne – EPFL), which aimed to develop the life sciences as well as the humanities and social sciences in the Lémanic region. The CIG has three main missions: • The pursuit of a first rate research program in the biological sciences • The development of an outstanding teaching program • The development and support of core facilities offering cutting-edge technologies to the Lémanic research com- munity and beyond The research at the CIG centers on genome structure and function in a number of different experimental systems and relies on a large number of different techniques. It is performed by an international community of scientists, yet the character of the CIG is one of an integrated research center, where interactions among groups are numerous both in formal and informal settings.

2 CIG 2007/2008 Scientific Advisory Committee members The Scientific Advisory

Prof. Robert EISENMAN Prof. Jacques SAMARUT* Committee (SAC) (President of the SAC) Director of the The CIG Scientific Advisory Committee (SAC) is a consultative com- Fred Hutchinson Cancer Ecole Normale Supérieure mission of external experts widely recognized for their contribution Research Center de Lyon, in the fields of activity of the CIG. Its principal responsibilities are : University of Washington Lyon, France School of Medicine, Seattle, USA • To advise on scientific objectives and priorities *until January 2009 • To evaluate the outcomes Prof. Steve BROWN* • To propose means of improving outcomes and visibility Director of the MRC Mammalian Prof. Ueli SCHIBLER • To propose the acquisition of new technologies or the Dpt of Molecular Biology and Genetics Unit Harwell development of new research and educational activities or NCCR Frontiers in Genetics Harwell, UK services University of Geneva *since January 2009 Geneva, Switzerland The members of the SAC visited the CIG in June 2007 and in June 2008. During these visits, they had discussions with the CIG Direc- tor, with each group leader, with the CIG students and postdoc- Dr Laurent DURET Prof. Ivan STAMENKOVIC toral fellows, and with members of the administrative and techni- Biometry and Evolutionary Director of the Dpt of cal staff. They also met with the Dean of the Faculty of Biology and Biology laboratory, CNRS Experimental Pathology Medicine. Université Claude Bernard Lyon I University of Lausanne (UNIL) Villeurbanne, France Lausanne, Switzerland Their conclusions and recommendations, which were each time summarized in a report, led to considerable improvements for the CIG in aspects as diverse as policies for promotion proposals or the Prof. Susan GASSER Prof. Markus STOFFEL establishment of a cozy “coffee corner” on the CIG main floor. Director of the Friedrich Miescher Institute of Molecular Their next visit is scheduled for 2010. Institute for Biomedical Research Systems Biology (FMI), Swiss Federal Institute of Basel, Switzerland Technology Zurich (ETHZ) Zurich, Switzerland

Prof. Ueli GROSSNIKLAUS Institute of Plant Biology Prof. Gisou VAN DER GOOT University of Zurich Global Health Institute Zurich, Switzerland Ecole Polytechnique Fédérale de Lausanne (EPFL) Lausanne, Switzerland

3 Introduction

Message from the Director

The Center for Integrative Genomics was started in 2002 with the speed. We can determine which genes are active when, when and appointment of its founding Director, Walter Wahli. This was fol- where specific proteins are bound to the genome, how these pro- lowed by a period of faculty recruitment as well as, starting in the teins are modified, all of this on a genomic scale. Progress in the pro- Fall of 2004, the extensive remodeling of the building now known teomics field allows the analysis of large mixture of proteins, indeed as the Génopode. These efforts culminated with the inauguration of of the entire proteome of a cell under various circumstances. With the CIG in October 2005. Thus, the CIG will enter its fourth year as such developments we can test the generality of mechanisms stud- a fully functional department in its own quarters in the Fall of 2009. ied until now in only a few model systems. We can also use these In the last two years, it has grown from thirteen to sixteen faculty large-scale data as a discovery tool, for example to compare the members and is now at full steam! Together with this growth in genomic landscapes of cells in different states. These developments the number of faculty members, the CIG has seen a steep increase also mean that an increasing number of large datasets produced for in its research activities as measured, for example, by the amounts a specific published study are accessible to other researchers who of external funds that have been raised. We have gone from about can then use the same data to answer another question. This activ- 35% of our UNIL budget in 2006 to close to 60% of this budget in ity of data mining will become more and more important for the 2008, and this number is likely to increase further in the next few advancement of any research project as the number of searchable years. Thus, the CIG is doing very well indeed and is well on its way datasets increases. to fulfilling its promise as a flagship research department of the We are indeed fortunate enough The new biology, the “omics” biology has important implications University of Lausanne (UNIL). to be biologists in a time of for the teaching of biology, as it demands skills from researchers remarkable advances in our field, Why put so much emphasis on research in universities, whose main that were dispensable in the days of “good old” molecular biology. function is, after all, the education of students? In fact, at the uni- Indeed, whereas the human brain can easily deal with a few data the time of “omics”. versity level, research is intimately linked to teaching and vice-versa. points, it is another story when an experiment produces from thou- On the one hand, the research carried out in our laboratories feeds sands to millions of data points. Thus, the composition of research Nouria Hernandez, CIG Director directly into our courses and allows us to teach at the cutting-edge groups involved in large scale experiments is, ideally, a mix of “wet of current knowledge. On the other hand, in an academic environ- lab” researchers, who deal with real molecules, cells, tissues, or organ- ment a large part of the research is conducted by people in training; isms, and the “dry lab” researchers, who deal with virtual molecules, master- and graduate students, postdoctoral fellows, and even tech- datafiles and databanks, scripts, and algorithms. In this ideal situation nician trainees! Without them, there would be little research indeed again, researchers are familiar with both the “wet” and “dry” aspects in universities! Teaching, and attracting the brightest students, is of the research and capable of carrying out both, even if each special- thus of paramount importance to maintain a high level of research, izes more in one aspect. The reality, however, is quite different. Most and vice-versa. The various CIG faculty members are now contrib- students studying molecular biology or biochemistry have little or no uting to teaching at the Bachelor, Master, and PhD levels, but our training in computational biology, even today. As a result, they lack next goal is the establishment of a flagship course or program that the proficiency to analyze their own large-scale experiments as well could be identified with the CIG. In thinking about such a program, as to take full advantage of published large datasets. In general, there it seems obvious that the role of the Center for Integrative Genomics is a lack of computational biologists in Switzerland, which will only should be to teach aspects of functional genomics, thus transmitting become more severe in the next few years. to the students the excitement of a biology revolution we are in the This is where I believe the CIG could make a unique contribution to midst of experiencing. teaching. Indeed, we have the privilege to be located in the same We are indeed fortunate enough to be biologists in a time of building as Vital-IT, the core facility of the Swiss Institute of Bioinfor- remarkable advances in our field, the time of “omics”. More than matics (SIB) dedicated to helping the biological sciences. Thanks to 800 microbial genomes have now been completely sequenced! For the concept of “embedded bioinformaticians” developed by Vital-IT eukaryotes, the number of completely sequenced genomes is 23, Director Ioannis Xenarios and SIB Director Ron Appel, the bioinforma- with another 251 at the assembly stage and 256 still in progress. The ticians hired in “wet research groups” can be part of the SIB and thus tools to analyze these genomes are evolving at an ever accelerating have access to its considerable computing resources and its expertise.

4 CIG 2007/2008 Highlights of 2007-2008

Moreover, some of the CIG groups already combine both expertise. This seems, then, like a perfect environment to develop a PhD pro- life at the CIG Faculty members achievements gram centered not on a specific biology subject but on the concept that, at graduation, the new PhD student is fluent both in experimen- R. Benton, S. Martin and A. Stasiak joined the CIG as group leaders • B. Desvergne was promoted to Full Professor tal “wet” research as well as in bioinformatics methods. According to • N. Hernandez was awarded the Cloëtta Prize 2007 taste and interests, the emphasis might be on one or the other, but Funding • N. Hernandez was elected member of the European Molecular both aspects will have been approached during the thesis. The CIG members attracted external research funds for about Biology Organization (EMBO) Concretely, how could such a program be established? The program 11.5 millions CHF, among which • W. Herr was appointed vice-Dean for Biology at the Faculty should be flexible enough to allow the participation of any labora- of Biology and Medicine (FBM), UNIL tory, be it a uniquely computational laboratory, a uniquely “wet” • an ERC Starting Independent Researcher Grant (R. Benton) • W. Herr was elected member of the European Molecular experimentation laboratory, or a laboratory with both expertise. • a Career Development Award from Human Frontier Science Biology Organization (EMBO) Depending on the expertise available in the chosen laboratory, a stu- Program (HFSP) (S. Martin) dent might conceivably have a second thesis advisor who would be • H. Kaessmann was titularized and is now Associate Professor • a Swiss National Science Foundation (SNSF) R’Equip grant for a collaborator on the project and might host the student for some • H. Kaessmann was awarded the Basic Life Science Research an Ultra High Throughput sequencing machine for the DAFL period of time. In any case, by the time of graduation, the student Award 2008, Faculty of Biology and Medicine (FBM), UNIL would have performed a research project involving both pipetting as (N. Hernandez, with I. Sanders (UNIL), D. Trono (EPFL), • W. Wahli was awarded the Hartmann-Müller Foundation well as battling with a computer keyboard! The CIG is looking for- S. Antonorakis (UNIGE)) prize 2008 ward to materialize such an exciting program. • W. Wahli was chosen as a member of the Swiss Science Nouria Hernandez, and Technology Council CIG Director

5 6 CIG 2007/2008 research 7 Research

Richard Benton Chemosensory perception in Drosophila : Assistant Professor from genes to behaviour

The overall goal of our research is to understand how sensory infor- • A key first step in understanding how information encoded by mation in the environment is detected and processed in the brain to peripheral chemosensory neurons is represented centrally is to evoke an appropriate behavioural response. We focus on the olfac- determine the neuroanatomical organisation of these circuits. tory and gustatory systems of the fruit fly, Drosophila melanogaster, We are generating genetic reagents in order to map the pro- a model genetic organism that displays a sophisticated repertoire jections of IR-expressing neurons in the brain. These tools will of chemosensory-driven behaviours under the control of neural cir- also allow us to examine their physiological properties by optical cuits that have similar anatomical and functional properties to those imaging and to manipulate their activity to determine their role of mammals but with significantly reduced complexity. Our group in mediating behaviour. takes a multidisciplinary approach to this problem, combining bioin- • Olfactory systems display remarkably rapid evolution, as organ- formatics, genetics, molecular cell biology, electrophysiology, neu- isms acquire and discard chemosensory receptors, neurons and ronal imaging and behavioural analysis. We aim to gain insights into responses with the ever-changing landscape of chemical stimuli both a fundamental problem of neuroscience - how genes and cir- cuits control behaviour – and the evolutionary mechanisms operat- in their environment. Insects provide an excellent opportunity to ing in animal nervous systems. Our work also has potential direct examine the genetic basis of these processes through the avail- application in the development of novel strategies to control the ability of the genome sequences of diverse insect species that chemosensory-driven behaviours of pest insects. have very different chemosensory sensitivities and preferences. Towards this, we have initiated bioinformatic and molecular The Ionotropic Receptors: a new family of analysis of the evolution of IR repertoires across insects. chemosensory receptors Functional analysis of a CD36 protein in We recently discovered a novel family of chemosensory genes, pheromone detection named the Ionotropic Receptors (IRs). These genes encode proteins that are structurally related to ionotropic glutamate receptors, a con- We are also studying the function of a CD36 protein named SNMP, served class of ligand-gated ion channel best studied for their roles which we showed has an essential, and likely widespread, role in in synaptic transmission. IRs, however, have highly divergent ligand insect pheromone detection. CD36 transmembrane receptors are binding domains that lack glutamate-interacting residues. IR genes widely conserved in metazoans and implicated in diverse processes are expressed in specific combinatorials in neurons in the antenna - such as lipid transport, bacterial immune recognition, phagocyto- the major olfactory organ - that are distinct from those that express sis of apoptotic cells and fat taste perception. Their precise molecu- the well-characterised Odorant Receptors (ORs). IRs localise to the lar role in any of these contexts is poorly understood. Our previous ciliated endings of olfactory sensory dendrites and expression of an studies defined SNMP as one of the best characterised CD36 pro- IR in an ectopic neuron is sufficient to confer novel odour respons- teins in an in vivo biological process, in which we know the identity es, providing evidence for a direct role in odour recognition. The of both physiologically-relevant extracellular ligands (pheromones) IRs are therefore likely to define a previously unappreciated second and downstream effector pathways (OR-mediated neuronal activi- Richard Benton received his PhD in 2003 from the University of “nose” in Drosophila. We are now using the IRs as a model system ty). Thus, SNMP represents a powerful system to dissect the molecu- Cambridge UK for work on the molecular mechanisms of cell polarisa- to study several aspects of the function and evolution of chemosen- lar function and specificity of this important class of proteins. tion with Daniel St Johnston at The Wellcome Trust/Cancer Research sory circuits: UK Gurdon Institute. For his post-doctoral research, he joined Leslie Vosshall’s laboratory at The Rockefeller University, New York, study- • How IRs transform ligand recognition into sensory neuron activ- ing the molecular biology of odour detection in Drosophila, during ity is unknown. We are combining structure-function analysis of which he was supported by fellowships from the European Molecular IRs in vivo and in vitro to determine whether these receptors act Biology Organisation and the Helen Hay Whitney Foundation. He joined as ion channels, the existence and functional specificity of dif- the Center for Integrative Genomics in September 2007 as Assistant ferent IR protein complexes and the molecular basis of IR ligand Professor and was awarded a European Research Council Starting recognition. Independent Researcher Grant in 2008.

8 CIG 2007/2008 Group members Publications Funding and Collaborations

Group leader research articles Funding Richard Benton Louis M, Huber T, Benton R, European Commission (FP7) [email protected] Sakmar TP, Vosshall LB (2008) European Research Council (ERC) Bilateral olfactory sensory input Starting Independent Postdoctoral fellows enhances chemotaxis behavior. Researcher Grant Yaël Grosjean Nat Neurosci 11:187-199 Swiss National Science Michael Reid Benton R, Vannice KS, Foundation (SNSF) Ana Florencia Silbering Vosshall LB (2007) R’Equip Grant for a 2-photon An essential role for a CD36- microscope PhD students related receptor in pheromone Roche Research Foundation Rati Bell detection in Drosophila. Nature PhD fellowship to R. Rytz Raphaël Rytz 450:289-293 Collaborations Masters students Benton R, Vannice KS, Gomez-Diaz C, Vosshall LB G. Jefferis Vincent Croset (2009) MRC-LMB, Cambridge, UK Deborah Widmer Variant ionotropic glutamate receptors as chemosensory Technician receptors in Drosophila. Cell Liliane Abuin 136:149-162

Secretary Reviews Annick Crevoisier Benton R (2008) [email protected] Chemical sensing in Drosophila. Curr Opin Neurobiol 18:357-363 Asahina K, Benton R (2007) Smell and taste on a high: symposium on chemical senses: from genes to perception. EMBO Rep 8:634-638 Benton R (2007) Sensitivity and specificity in Drosophila pheromone perception. Trends Neurosci 30:512-519

9 Research

Béatrice Desvergne Networking activity of PPARs during development and in adult Professor metabolic homeostasis

As they mediate intracellular hormone action, nuclear receptors play a The role of PPARs as mediating the activity of some endocrine dis- crucial multi-faceted role in coordinating growth during development, ruptors was an important focus of our recent activity. To understand and homeostasis at adult stage. Among them, the peroxisome-prolif- how endocrine disruptors behave at the molecular levels in the living erator activated receptors (PPARs) act as fatty acids sensors, respond- cells, we used a combination of Fluorescence Recovery After Photo- ing to dietary as well as to endogenous challenges. Accordingly, they bleaching (FRAP), Fluorescence Correlation Spectroscopy (FCS) and have an integrative role in controlling the expression of genes regulat- Fluorescence Resonance Energy Transfer (FRET). We first demonstrat- ing the storage, mobilization, and/or utilization of lipids. Using various ed that PPARs readily heterodimerize with retinoid X receptor (RXR) molecular, cellular, and animal approaches, our studies are aimed at and exhibit a ligand-induced reduction of mobility, probably due understanding how PPARs are integrated in the main pathways that to enhanced interactions with cofactors and/or chromatin. We also shape the organism during development on the one hand and main- demonstrated that coregulator recruitment (and not DNA binding) tain systemic homeostasis on the other hand. plays a crucial role in receptor mobility, suggesting that transcrip- tional complexes are formed prior to promoter binding. This allowed We were among the first to generate PPAR mutant mice. Following us to demonstrate that, in the living cells, the pollutant monoethyl- a clinician-type of approach, our activities have been centered on hexyl-phthalate (MEHP) directly binds to the ligand binding domain revealing and understanding at the molecular levels the phenotypic of PPAR and drives the recruitement of a specific subset of cofactors. expressions of PPAR mutations, taking them as leads to explore the We further analyzed the consequences in vivo of such activities and physiopathological significance and novel therapeutic advances that showed that MEHP protects mice from diet-induced obesity via a PPARs carry. PPARα-dependent activation of hepatic fatty acid catabolism. This Our studies during development show that both PPARβ and PPARγ is accompanied by, and possibly due to, the up-regulation of the are required for placenta development but each has specific activi- anti-obesity factor FGF21 hepatic expression. However, both effects ties: on the differentiation of trophoblast giant cells, via activation are reversed in PPARα-humanized mice, underlining the importance of the PI3K pathway and inhibition of Id2 for PPARβ, and on vas- of PPARα species-specific activities and questioning the impact of cular development via controlling the expression of angiogenic fac- phthalates in human metabolic homeostasis. tors for PPARγ. Further studies of the role of PPARβ and PPARγ in development were impeded by a partially and fully penetrant lethal- ity of PPARβ-/- and PPARγ-/- embryos, respectively, at embryonic day 10.5. However, we have now generated fully viable mutant embryos and live pups, through an epiblastic selective PPAR deletion. It dem- onstrates that the cause of embryonic lethality in PPAR mutants is mainly due to the placental defects and gives us new tols for explor- ing the role of PPARγ in late development and in adult tissues. In the adult animals, the gut is a very interesting organ, combining critical metabolic functions and a tightly regulated and highly active Béatrice Desvergne was trained as a MD. She initially specialized in cell renewal capacity, from few adult stem cells to highly differen- Anesthesiology and Resuscitation, practiced medicine for a few years, tiated enterocytes, Paneth, Goblet, and enterodendocrine cells. In and decided to move for fundamental research. She then carried out this tissue, we demonstrated that decrease of Indian Hedgehog via a post-doctoral stay from 1988 to 1992 at the National Institutes of PPARβ ensures the final maturation of Paneth cell precursors where- Health in Bethesda, first as visiting fellow and then visiting associate as PPARγ is rather involved in controlling inflammation processes. in the National Institute of Diabetes and Digestive and Kidney Diseases. We are now further exploring the importance of PPARs in response In 1992, she was appointed as Assistant Professor at the Institute to challenges, either metabolic, infectious, or physical damages, of Animal Biology of the UNIL. After being appointed as Associate with the purpose of bringing our mechanistic approaches in mouse Professor, she was promoted as full Professor in 2008. She joined the models closer to human pathologies. Center for Integrative Genomics in 2003.

10 CIG 2007/2008 Group members Publications Funding and Collaborations

Group leader research articles Feige JN, Gelman L, Rossi D, bral ischemia in peroxisome Rotman N, Terreau-Haftek Z, Funding Béatrice Desvergne *Michalik L, *Zoete V, Krey Zoete V, Metivier R, Tudor C, proliferator-activated receptor Lücke S, Feige J, Gelman L, Swiss National Science [email protected] G, Grosdidier A, Gelman L, Anghel SI, Grosdidier A, (PPAR)-deficient mice. NMR Desvergne B, Wahli W (2008) Foundation (SNSF) Chodanowski P, Feige JN, Lathion C, Engelborghs Y, Biomed 20:335-342 PPAR diruption: cellular mecha- Independent Basic Postdoctoral fellows Desvergne B, **Wahli W, Michielin O, Wahli W, Tudor C, Feige JN, Pingali H, nisms and physiological conse- Research Grant Elodie Bedu* **Michielin O (2007) Desvergne B (2007) Lohray VB, Wahli W, quences. CHIMIA 62:340-344. European Commission (FP6) Cristina Casals Casas Combined simulation and The endocrine disruptor Desvergne B, Engelborghs Y, Desvergne B (2007) Project SOUTH Jérôme Feige* mutagenesis analyses reveal monoethyl-hexyl-phthalate is a Gelman L (2007) PPARs special issue: anchor- Federation of European Christophe Héligon the involvement of key residues selective peroxisome proliferator- Association with coregulators is ing the present to explore the Biochemical Societies (FEBS) Karim Nadra* for peroxisome proliferator- activated receptor gamma the major determinant governing future. Biochim Biophys Acta Postdoctoral fellowship Laure Quignodon activated receptor alpha helix 12 modulator that promotes peroxisome proliferator-activated 1771:913-914 to L. Quignodon adipogenesis. J Biol Chem Frédéric Varnat* dynamic behavior. J Biol Chem receptor mobility in living cells. Desvergne B (2007) 282:19152-19166. 282:9666-9677. J Biol Chem 282:4417-4426. RXR: From Partnership to Lead- Collaborations PhD students Indra AK, Castaneda E, Anghel SI, Bedu E, Vivier CD, Wang H, Xie H, Sun X, ership in Metabolic Regulations. F. Ali Antal MC, Jiang M, Imtiyaz Ahma* Descombes P, Desvergne B, Tranguch S, Zhang H, Jia X, Vitam Horm 75:1-32 Imperial College School of Messaddeq N, Meng X, Jean-Marc Brunner Wahli W (2007) Wang D, Das SK, Desvergne B, Gelman L, Feige JN, Medicine, London, UK Loehr CV, Gariglio P, Kato S, He Fu Adipose tissue integrity as a Wahli W, Dubois RN, Dey SK Desvergne B (2007) Wahli W, Desvergne B, E. Chamaillard, P. Desreumaux Matthew Hall prerequisite for systemic energy (2007) Molecular basis of selec- Metzger D, Chambon P (2007) and L. Dubuquoy Sajit Thottathil Oomment balance: a critical role for peroxi- Stage-specific integration tive PPARgamma modulation Malignant transformation of Université de Lille, France some proliferator-activated of maternal and embryonic for the treatment of Type 2 Trainees DMBA/TPA-induced papillomas A.-M. Cimini receptor gamma. J Biol Chem PPARdelta signaling is critical to diabetes. Biochim Biophys Acta and nevi in the skin of mice Università di L’Aquila, Italy Alan Gerber* 282:29946-29957 pregnancy success. J Biol Chem 1771:1094-1107 Chiara Sardella selectively lacking retinoid-X- 282:37770-37782. M. Crestiani Bedu E, Desplanches D, receptor alpha in epidermal Zhenghui Wang* Pequignot J, Bordier B, comment University of Milan, Italy keratinocytes. J Invest Dermatol Reviews Desvergne B (2007) Desvergne B (2007) Y. Enghelborgs Technicians 127:1250-1260. * * Double gene deletion reveals Hall MG, Quignodon L, Retinaldehyde: more than Université de Leuven, Belgique Mandard S, Stienstra R, Desvergne B (2008) Geneviève Metthez* the lack of cooperation between meets the eye. Nat Med F. Gonzalez Escher P, Tan NS, Kim I, Peroxisome Proliferator-Activated Carine Winkler PPARalpha and PPARbeta in 13:671-673 National Institutes of Health Gonzalez FJ, Wahli W, Receptor beta/delta in the Brain: skeletal muscle. Biochem Biophys (NIH), Bethesda, USA Secretary Res Commun 357:877-881 Desvergne B, Muller M, Facts and Hypothesis. PPAR Res *both authors contributed equally Marlène Petit Kersten S (2007) 2008:780452 S. Kersten Berry A, Balard P, Coste A, to this work. University of Wageningen, [email protected] Glycogen synthase 2 is a Casals-Casas C, Feige JN, Olagnier D, Lagane C, novel target gene of peroxisome The Netherlands Authier H, Benoit-Vical F, Desvergne B (2008) **joint senior authors. proliferator-activated receptors. R. Métivier *left the group Lepert JC, Seguela JP, Interference of pollutants with Cell Mol Life Sci 64:1145-1157. Université de Rennes, France Magnaval JF, Chambon P, PPARs: endocrine disruption Metzger D, Desvergne B, Pialat JB, Cho TH, Beuf O, meets metabolism. Int J Obes J.A. Mitchell Wahli W, Auwerx J, Joye E, Moucharaffie S, (Lond) 32 Suppl 6:S53-61 Imperial College School Pipy B (2007) Langlois JB, Nemoz C, Desvergne B (2008) of Medicine, London, UK IL-13 induces expression of Janier M, Berthezene Y, PPARdelta/beta: the lobbyist CD36 in human monocytes Nighoghossian N, switching macrophage alle- through PPARgamma activation. Desvergne B, Wiart M (2007) giance in favor of metabolism. Eur J Immunol 37:1642-1652. MRI monitoring of focal cere- Cell Metab 7:467-469

11 Research

Christian Fankhauser The effects of light on plant growth and development Associate Professor

Almost all our food, feed, fuel and fiber ultimately derives from opening of stomata the phototropins largely contribute to the opti- plants. The growth of plants depends on photosynthesis, the pro- mization of photosynthesis. Interestingly the phototropic response cess in which light energy is harnessed for the synthesis of high is co-ordinately controlled by the phototropins and the phyto- energy reduced carbon compounds. In order to capture light, plants chromes (in part indirectly by inhibiting the gravitropic response of have evolved unique ways of building cells, tissues and organs, a the hypocotyl). highly diverse metabolism, and a life-long continuation of versatile We combine molecular genetics, genome-wide expression studies, growth and development. Given the central importance of light for cell biology and biochemistry in Arabidopsis to address the follow- growth, plants possess numerous photoreceptors enabling them to ing specific aims: sense changes in the amount, quality (color), photoperiod and direc- tion of light. The main goal of our research is to understand how • Identify the molecular determinants leading to the specificity light modulates plant growth and development in order to allow of phyA. Unlike other phytochromes, phyA can mediate light these sessile organisms to optimize their growth habit depending on responses under conditions where the vast majority of the the environmental conditions. We use the model plant Arabidopsis phytochrome is in its inactive Pr state. This correlates with the thaliana for our research. unique ability of phyA to accumulate in the nucleus in far-red Molecular genetic studies in Arabidopsis have identified four pho- light (mimicking light under a dense canopy). toreceptor families that are present in all higher plants. There are • Determine the mechanisms by which the phytochromes con- three classes of blue light sensors: cryptochromes, phototropins and trol PIF-mediated growth responses. We mostly concentrate members of the Zeitlupe family. In addition plants sense red and our attention on the role of PIF4 and PIF5 in the regulation of far-red light with the phytochromes. In Arabidopsis these families growth during the shade avoidance response. are composed of three cryptochromes (cry1-cry3), two phototro- pins (phot1 and phot2), three Zeitlupe-like sensors and five phyto- • Uncover the mode of action of PKS (Phytochrome Kinase Sub- chromes (phyA-phyE). strate) proteins in the control hypocotyl growth orientation. Proper positioning of the stem is of central importance for the In our lab we concentrate our attention on phytochrome and pho- plant in order to optimize photosynthetic light capture. PKS totropin-mediated signal transduction. Phytochromes are synthe- proteins are involved both in phytochrome and phototropin sized as Pr (R light absorbing); upon light excitation they are pho- signalling and may thus allow us to understand how these two to-transformed into Pfr (FR light absorbing), which is the active photoreceptors co-ordinately control this growth response. Pho- conformer. Light activation of the phytochromes triggers their accu- totropism requires asymmetric growth of the shaded and lit sides mulation in the nucleus where they mediate large changes in light- of the hypocotyl. An important goal is to understand how this regulated gene expression. This activity is partly mediated by the light response ultimately leads to asymmetric distribution of the conformation-specific interaction between Pfr phytochromes and plant hormone auxin, which is required for directional growth. a family of bHLH class transcription factors known as PIFs (Phyto- chrome Interacting Factor). Photon capture by these photoreceptors induces a suite of developmental responses including seed germi- nation, seedling de-etiolation, regulation of tropic growth, shade Christian Fankhauser received his PhD from the UNIL in 1994 after avoidance and the control of flowering time. Some light responses carrying out his thesis at Swiss Institute for Experimental Cancer are specifically induced by a single phytochrome (for example only Research (ISREC) in the laboratory of Dr. Viesturs Simanis. He per- phyA can trigger the de-etiolation response under a dense canopy), formed postdoctoral studies with Dr. Marty Yanofsky at UCSD then but there are many examples where integration of signals emanat- with Dr. Joanne Chory at The Salk Institute for Biological Studies in ing from multiple photoreceptors is required. The phototropins are San Diego. He became a Swiss National Science Foundation Assistant blue-light activated protein kinases composed of two light-sensing Professor at the Department of Molecular Biology of the University LOV domains and a carboxy-terminal protein kinase domain. By con- of Geneva in 2000. He joined the Center for Integrative Genomics in trolling phototropism, leaf positioning, chloroplast movements and January 2005, where he was appointed Associate Professor.

12 CIG 2007/2008 Group members Publications Funding Collaborations

Group leader Summer Students research articles Lorrain S, Allen T, Duek PD, Swiss National Science Y. Barral Christian Fankhauser Vanja Vukojevic (2007) Boccalandro HE, De Simone SN, Whitelam GC, Fankhauser C Foundation (SNSF) ETHZ, Zurich, Switzerland [email protected] Fang Wang (2008) Bergmann-Honsberger A, (2008) • Independent Basic J. Casal Schepens I, Fankhauser C, Phytochrome-mediated Research Grant University of Buenos Aires, Postdoctoral fellows TechnicianS Casal JJ (2008) inhibi­tion of shade avoidance • National Centers of Argentina involves degradation of growth- Competence in Research Emilie Demarsy Laure Allenbach1 PHYTOCHROME KINASE P. Davis promoting bHLH transcription (NCCR) Plant Survival Thierry Genoud* Martine Trevisan1 SUBSTRATE1 regulates root University of Indiana, factors. Plant J 53:312-323 Chitose Kami phototropism and gravitropism. SystemsX.ch Bloomington, USA Séverine Lorrain Apprentices technician Plant Physiol 146:108-115 Schepens I, Boccalandro HE, Project Plant Growth in a M. Geisler and E. Martinoia Isabelle Schepens* Angélique Vaucher* de Lucas M, Daviere JM, Kami C, Casal JJ, Changing Environment University of Zurich, Switzerland Laurie Vuillet Philippe Kirchner* Rodriguez-Falcon M, Pontin M, Fankhauser C (2008) Faculty of Biology and U. Genick Céline Wyser Iglesias-Pedraz JM, Lorrain S, PHYTOCHROME KINASE Medicine (FBM), UNIL University of Brandeis, PhD students Fankhauser C, Blazquez MA, SUBSTRATE 4 modulates Interdisciplinary research project Artist in Residence Titarenko E, Prat S (2008) phytochrome-mediated control Waltham, USA Dimitry Debrieux European Molecular Biology A molecular framework for light of hypocotyl growth orientation. R. Hangarter Matthieu De Carbonnel Sylvia Hostettler* Organization (EMBO) and gibberellin control of cell Plant Physiol 147:661-71 University of Indiana, Vincent Fiechter* (project “Artists in labs”) Long term fellowship to elongation. Nature 451:480-484 Bloomington, USA Patricia Hornitschek Nozue K, Covington MF, L. Vuillet Secretary Fiechter V, Cameroni E, Duek PD, Lorrain S, R. Hedrich Human Frontier Science Masters students Nathalie Clerc Cerutti L, De Virgilio C, Fankhauser C, Harmer SL, University of Würzburg, Germany Program (HFSP) Andrea Maran* [email protected] Barral Y, Fankhauser C (2008) Maloof JN (2007) Young Investigator Award 2004 A. Hiltbrunner Fabian Schweizer* The evolutionary conserved Rhythmic growth explained by University of Freiburg, Germany Roche Research Foundation *left the group BER1 gene is involved in mi­ coincidence between internal crotubule stability in yeast. and external cues. Nature • Postdoctoral fellowship to J. Maloof 1 part-time Curr Genet 53:107-115 448:358-361 S. Lorrain University of California, Davis, USA • PhD fellowship to Genoud T, Santa Cruz MT, Trupkin SA, Debrieux D, S. Prat P. Hornitschek Kulisic T, Sparla F, Hiltbrunner A, Fankhauser C, Centro National de Fankhauser C, Casal JJ (2007) Toboyo Foundation Biotechnologia, Madrid, Spain Metraux JP (2008) The serine-rich N-terminal region Postdoctoral fellowship R. Roelfsema The protein phosphatase 7 of Arabidopsis phytochrome to C. Kami University of Würzburg, Germany regulates phytochrome signaling A is required for protein stability. E. Schaefer in Arabidopsis. PLoS ONE Plant Mol Biol 63:669-678 University of Freiburg, Germany 3:e2699 Review K. Shimazaki Genoud T, Schweizer F, Kyushu University, Fukuoka, Japan Tscheuschler A, Debrieux D, Fankhauser C, Chen M (2008) C. de Virgilio Casal JJ, Schafer E, Transposing phytochrome into University of Fribourg, Switzerland Hiltbrunner A, the nucleus. Trends Plant Sci Fankhauser C (2008) 13:596-601 G. Whitelam FHY1 mediates nuclear import of University of Leicester, UK the light-activated phytochrome A photoreceptor. PLoS Genet 4:e1000143

13 Research

Paul Franken Genetics and energetics of sleep homeostasis Maître d’Enseignement et de Recherche and circadian rhythms

In the study of sleep two main regulatory processes have to be con- gene expression to the time–spent–awake. The observation that the sidered: a homeostatic process that is activated by and counters the transcriptional activity of CLOCK and NPAS2 depends on and affects effects of sleep loss and a circadian process that determines the intracellular energy charge is an exciting first clue because this time–of–day sleep preferably occurs. The fine–tuned interaction would represent a direct molecular link between cellular metabo- between the two permits us to stay awake and alert throughout the lism and the need for sleep. We are currently investigating this issue day and to remain asleep at night. To gain inside into the molecular using redox–sensitive GFP probes and developing in vivo imaging correlates of the homeostatic process and its interaction with the cir- techniques to simultaneously monitor intracellular redox state and cadian process we apply a combination of forward, molecular, and PER2 levels in freely moving mice. We previously established that reverse genetic approaches in the mouse. the sleep-wake dependent changes in Per1 and Per2 are, in part, mediated by their transcriptional regulator NPAS2. Using chromatin QTL mapping immunoprecipitation (ChIP) sequencing we aim to indentify which other NPAS2 target genes are differently regulated with sleep loss. We use Quantitative Trait Loci (QTL) analysis as a forward genetics Finally, using mathematical modeling we are now quantifying the tool to map genomic regions that affect sleep. A first mouse refer- complex relationship between changes in clock gene expression in ence population we used is a panel of recombinant inbred (RI) lines the forebrain and the sleep-wake distribution in a similar way as we derived from the inbred strains C57BL/6J and DBA/2J referred to as previously have quantified the relationship between the sleep-wake BXD mice. The analyses revealed several genomic regions affecting distribution and the EEG correlates of sleep need in mice. Model sleep and EEG traits. Especially EEG traits were found to be under predictions are useful in helping to design relevant experiments to strong genetic control. Thus far, we were successful at identifying the unravel these non-linear relationships. genes modifying two such traits thereby implicating novel signaling pathways involved in rhythmic brain activity. Ongoing work focuses on the Dps1 QTL on chromosome 13 that alters sleep homeostasis and for which Homer1 is a good candidate gene. In addition, we are now initiating two large scale projects to phenotype and map sleep traits in other mouse reference populations (i.e., CFW outbred mice and the ‘Collaborative Cross’ RI lines). To facilitate the phenotyping of large numbers of mice we helped develop and validate a novel non-invasive and high throughput method to measure sleep.

Clock genes & sleep homeostasis Paul Franken received his PhD from the University of Groningen, Although the circadian and homeostatic processes are thought to The Netherlands, in 1993 for his work on sleep homeostasis and operate independently, using reverse (‘knock out’) and molecular thermoregulation at the University of Zurich under the direction of genetics (qPCR, micro-array) approaches, we found that the genes Alexander A. Borbély. He was a postdoctoral fellow with H. Craig Heller known to set circadian time (referred to as clock genes) are also at Stanford University, USA, where he studied the cellular mecha- involved in the homeostatic regulation of sleep. Thus, in mice lack- nisms underlying circadian clock resetting. In 1996 he joined Mehdi Tafti ing one or a combination of two of the core clock components (e.g. at the University of Geneva where he used QTL analysis to map sleep Clock, Npas2, Bmal1, Cry1 and Cry2) sleep homeostasis is altered. and EEG traits in mice. He then moved back to Stanford in 2000 We also showed that the expression of the clock genes Per1 and as a senior research scientist to establish an independent lab. At Per2 in the forebrain is tightly linked to the prior sleep–wake history. Stanford he continued to work on the genetics of sleep homeostasis Thus contrary to the prevailing notion that circadian and homeo- and further focused on the molecular interactions between circa- static processes are separate, at a cellular level the same molecular dian rhythms, sleep homeostasis, and brain metabolism. He joined circuitry seems to be implicated in both circadian rhythms and sleep the CIG in 2005. homeostasis. We now investigate the mechanisms that link clock

14 CIG 2007/2008 Group members Publications Funding and Collaborations

Group leader research articles Maret S, Dorsaz S, Gurcel L, Funding Paul Franken Cueni L, Canepari M, Lujan R, Pradervand S, Petit B, Pfister C, Swiss National Science [email protected] Emmenegger Y, Watanabe M, Hagenbuchle O, O’Hara BF, Foundation (SNSF) Bond CT, Franken P, Franken P, Tafti M (2007) Independent Basic Postdoctoral fellows Adelman JP, Luthi A (2008) Homer1a is a core brain Research Grant molecular correlate of sleep Thomas Curie T-type Ca(2+) channels, SK2 National Institutes of Health Stéphanie Maret* channels and SERCAs gate loss. Proc Natl Acad Sci U S A 104:20090-20095 (NIH), USA Valérie Mongrain sleep-related oscillations in Independent Basic thalamic dendrites. Nat Neurosci Reviews Research Grant PhD student 11:683-92 Andretic R, Franken P, Tafti M European Commission (FP6) Francesco La Spada Wisor JP, Pasumarthi RK, (2008) Project EuMODIC Gerashchenko D, Thompson CL, Genetics of sleep. Annu Rev European Commission (FP7) Technician Pathak S, Sancar A, Franken P, Genet 42:361-388 Marie Curie Intra-European Yann Emmenegger Lein ES, Kilduff TS (2008) Fellowship to T. Curie Sleep deprivation effects on O’Hara BF, Ding J, Bernat RL, Apprentice technician circadian clock gene expression Franken P (2007) Novartis Foundation Bartosz Wierzbicki* in the cerebral cortex parallel Genomic and proteomic ap- Research Fellowship to T. Curie electroencephalographic differ- proaches towards an under- Hoffmann-La Roche Secretary ences among mouse strains. J standing of sleep. CNS Neurol Collaborative Research Project Annick Crevoisier Neurosci 28:7193-7201 Disord Drug Targets 6:71-81 [email protected] Flores AE, Flores JE, Tafti M, Franken P (2007) Collaborations Molecular analysis of sleep. Deshpande H, Picazo JA, U. Albrecht Time course of the effects of a novel wake promoting drug on the EEG activity during Cold Spring Harb Symp Quant *left the group Xie XS, Franken P, Heller HC, University of Fribourg, wakefulness in three inbred strains of mice. Changes from baseline in EEG spectral Grahn DA, O’Hara BF (2007) Biol 72:573-578 profiles are plotted as a heat map, with colder (darker) colors indicating reduced EEG Switzerland Pattern recognition of sleep power density and warmer colors increased power density. J. Flint in rodents using piezoelectric Book chapter University of Oxford, UK signals generated by gross body Franken P (2008) movements. IEEE Trans Biomed Sleep Homeostasis. In: Encyclo- H.C. Heller Eng 54:225-233 pedia of Neuroscience. Edited Stanford University, USA Franken P (2007) by Binder MD, Hirokawa N, A. Lüthi The quality of waking and Windhorst U. Springer, Berlin UNIL, Lausanne, Switzerland Heidelberg New York. process S. Sleep 30:126-127 B.F. O’Hara Franken P, Thomason R, University of Kentucky, Heller HC, O’Hara BF (2007) Lexington, USA A non-circadian role for clock- D. Rector genes in sleep homeostasis: a Washington State University, USA strain comparison. BMC M. Tafti Neurosci 8:87 UNIL, Lausanne, Switzerland

15 Research

Nouria Hernandez Mechanisms of basal and regulated RNA polymerase II and III Professor transcription of ncRNA genes in mammalian cells

The task of transcribing the human genome is shared among three i) the RNAP-III transcription factors Brf1 and Bdp1; main RNA polymerases (RNAPs) known as RNAP-I, -II, and -III, as ii) RNAP-III itself; and iii) the five SNAP subunits. The results showed well as a newly identified single polypeptide RNAP-IV. RNAP-I tran- c nearly perfect colocalization of Brf1, Bdp1, and RNAP-III on RNAP- scribes the repeated 45S transcription unit, which gives rise to the III promoters, and good colocalization of the various SNAP sub- 28S, 18S, and 5.8S ribosomal RNAs. RNAP-II transcribes the mRNA c units on both RNAP-II and RNAP-III snRNA promoters. We are genes encoding proteins as well as most small nuclear RNA (snRNA) now extending this work to the entire genome using the ChIP-Seq and microRNA genes. Thus, in contrast to RNAP-I, RNAP-II recogniz- methodology. es a large variety of promoter structures, reflecting the intricate reg- ulation of its target genes in processes such as cell growth, prolifera- tion, differentiation, and responses to various stresses. spRNAP-IV is Activation of RNAP-III type 3 promoters thought to transcribe a few hundred mRNA-encoding genes. RNAP- and RNAP-II snRNA promoters III transcribes a collection of short genes encoding RNAs that are Our studies on the mechanisms of transcription activation have been essential for cellular metabolism as well as some regulatory RNAs centered on the role of the zinc finger protein Staf in activating tran- such as microRNAs. scription from the RNAP-III U6 promoter. We found that Staf can We are interested in mechanisms of transcription regulation of bind to preassembled chromatin templates and activate transcription genes producing transcripts that do not code for proteins, so-called in vitro, suggesting that it recruits activities that modify the chroma- non-coding RNA (ncRNA) genes. In particular we study the mecha- tin. Indeed, purification of Staf-associated proteins and their identifi- nisms that govern transcription of RNAP-II snRNA genes as well as cation by multi-dimensional protein identification technology (Mud- transcription of RNAP-III genes, which according to current knowl- PIT) revealed a number of proteins linked to chromatin remodeling edge all give rise to ncRNAs. Both classes of genes are relatively and histone modification, among them the chromodomain-helicase- understudied compared to classical RNAP-II mRNA-encoding genes, DNA binding protein 8 (CHD8). We showed that CHD8 binds to his- yet their regulation is of great importance for cell metabolism. Our tone H3 di- and tri- methylated on lysine 4, resides on the human recent focus has been in U6 promoter as well as on the mRNA IRF3 promoter in vivo, and is involved in efficient transcription from both these promoters. This i) the determination of the RNAP-III transcriptome in the human suggests that RNAP-III transcription requires chromatin remodeling genome, and uses some of the same factors used for chromatin remodeling ii) the mechanisms of transcription activation of RNAP-III snRNA pro- at RNAP-II promoters. moters, and

iii) the unexpected role of a subunit of the snRNA activating protein An unexpected function for a subunit of SNAPc complex (SNAP ), a transcription factor binding to the RNAP-II and c The unexpected role of a SNAP subunit was discovered during a rou- RNAP-III core snRNA promoters. c tine examination of SNAP localization. We found that the SNAP45 Nouria Hernandez performed her thesis research on mRNA splicing c subunit localizes to centrosomes during parts of mitosis, as well as with Dr. Walter Keller at the University of Heidelberg in Germany Targets for basal transcription factors used by to the spindle midzone during anaphase and the mid-body during and received her PhD in 1983. She did her postdoctoral studies with RNAP-II snRNA promoters and RNAP-III promoters telophase. Consistent with localization to these mitotic structures, Dr. Alan M. Weiner at Yale University in New Haven, Connecticut, both down- and up-regulation of SNAP45 led to a G2/M arrest with USA, working on 3’ end formation of the U1 small nuclear RNA. In collaboration with Dr. H. Stunnenberg, Radboud University, we set out to characterize targets for SNAP and RNAP-III in the human cells displaying abnormal mitotic structures. In contrast, down-reg- She then joined Cold Spring Harbor Laboratory at Cold Spring Harbor, c ulation of SNAP190, another SNAP subunit, led to an accumulation New York, in 1986 as an Assistant Professor. She became a Cold genome. We used an anti-TBP antibody we developed many years c of cells with a G0/G1 DNA content. Thus, SNAP45 seems to play two Spring Harbor Laboratory Professor in 1993 and joined the Howard ago to select TBP-binding fragments and create a DNA array, which roles in the cell, one as a subunit of the transcription factor SNAP , Hughes Medical Institute as an Associate Investigator in 1994. She was then probed with DNA from chromatin immunoprecipitations c and another as a factor required for proper mitotic progression. became a full Howard Hughes Medical Institute Investigator in 1999. performed with antibodies directed against various transcription In 2005, she joined the faculty of the UNIL as a Professor and as the factors including: Director of the Center for Integrative Genomics (CIG).

16 CIG 2007/2008 Group members Publications Funding Collaborations

Group leader Bioinformatician research articles research articles Swiss National Science C. Carles Nouria Hernandez Viviane Praz Shanmugam M, by hernandez group Foundation (SNSF) CEA, Saclay, France [email protected] Hernandez N (2008) members • Independent Basic I. Grummt Technicians Mitotic functions for SNAP45, Bierhoff H, Dundr M, Research Grant German Cancer Research • Maître assistant Pascal Cousin a subunit of the small nuclear Michels AA, Grummt I (2008) R’équip grant: Genome Center, Heidelberg, Germany structure, function, and Erwann Vieu Philippe L’Hôte1 RNA-activating protein Phosphorylation by casein kinase H. Stunnenberg regulation, with I. Sanders Apprentices technician complex SNAPc. J Biol Chem 2 facilitates rRNA gene transcrip- Radboud University, (UNIL), D. Trono (EPFL), Postdoctoral fellows Marion Graf* 283:14845-14856 tion by promoting dissociation Nijmegen, The Netherlands S. Antonorakis (UNIGE) Teldja Neige Azzouz* Céline Wyser* Denissov S, van Driel M, of TIF-IA from elongating RNA Diane Buczynski-Ruchonnet Voit R, Hekkelman M, Hulsen T, polymerase I. Mol Cell Biol SystemsX.ch Donatella Canella Secretary Hernandez N, Grummt I, 28:4988-4998 PhD project, 2nd mentor st Wassim Hodroj Nathalie Clerc Wehrens R, Stunnenberg H Michels AA, (1 mentor Alexandra Radenovic, Nicole James Faresse [email protected] (2007) Bensaude O (2008) EPFL, Lausanne) Annemieke Michels Identification of novel functional RNA-driven cyclin-dependent European Commission (FP6) *left the group TBP-binding sites and general kinase regulation: when CDK9/ Marie Curie Intra-European PhD students **changed function factor repertoires. Embo J cyclin T subunits of P-TEFb meet Fellowship to A. Michels Jaime Humberto Reina 26:944-954 their ribonucleoprotein partners. National Institutes of Health ** 1part-time Marianne Renaud Yuan CC, Zhao X, Florens L, Biotechnol J 3:1022-1032 (NIH), USA Swanson SK, Washburn MP, Project: Expression of Masters students Hernandez N (2007) snRNA genes Henrietta Hrobova Crausaz* CHD8 associates with human Roche Research Foundation Marianne Renaud** Staf and contributes to efficient • Postdoctoral fellowship Claire Bertelli* U6 RNA polymerase III transcrip- to T.N. Azzouz tion. Mol Cell Biol 27:8729-8738 Student trainee • PhD fellowship to J. Reina Aurélie Comte* Review Reina JH, Hernandez N (2007) Summer student On a roll for new TRF targets. * Jovan Mircetic Genes Dev 21:2855-2860

17 Research

Winship Herr Regulation of cell proliferation Professor

Two complete sets of instructions contained within the genomes we As indicated above, HCF-1 function is conserved in animals. We inherit from our parents are responsible for directing a single cell – take advantage of this property to perform genetic, genomic, bio- the zygote – to become an adult human being. This process results chemical, bioinformatic, and molecular studies in diverse organisms from controlled patterns of gene expression that are maintained as including the C. elegans worm and Drosophila fruit fly. Our recent well as changed during many rounds of cell division, differentiation, studies have benefited from such inter-species studies in flies and and death. Control of gene transcription is fundamental to these worms. For example, in flies, we have learned about mechanisms processes, with genetic and epigenetic defects in transcriptional reg- of HCF-1 proteolytic maturation. We have demonstrated that the ulation often leading to human disease including cancer. Drosophila MLL and HCF-1 homologs, called Trithorax and dHCF, are both cleaved by Drosophila Taspase1 — Taspase1 being the To investigate these processes, we study a key regulator of human- protease in human cells previously shown to cleave MLL proteins. cell proliferation that is also implicated in embryonic stem cell main- Although highly related, the human and Drosophila Taspase1 pro- tenance and cancer. This protein, called HCF-1 for herpes simplex teins display cognate species specificity: Thus, human Taspase1 virus host-cell factor-1, binds to many promoters indirectly by recog- preferentially cleaves human MLL and Drosophila Taspase1 prefer- nizing site-specific DNA-binding proteins and recruits histone-mod- entially cleaves the fly Trithorax protein, consistent with co-evolu- ifying activities [e.g., Sin3 histone deacetylase and mixed-lineage tion of Taspase1 and Trithorax-related proteins. leukemia (MLL) family of histone methyltransferases] for repression and activation of transcription. After synthesis, HCF-1 is cleaved into In contrast, HCF proteins display even greater species-specific diver- two subunits by an unusual process of proteolytic maturation. These gence in processing. Thus, dHCF is cleaved by the Drosophila Tas- two subunits remain associated but regulate different phases of the pase1 but human and mouse HCF-1 maturation does not involve human cell cycle: The N-terminal subunit permits cells to progress mammalian Taspase1. Instead, an in vitro HCF-1 cleavage assay into S phase for genome replication and the C-terminal subunit is shows that vertebrate HCF-1 proteins are cleaved by a novel pro- required for proper segregation of the replicated genome into the teolytic activity. Thus, from insects to humans, HCF proteins have two daughter cells in M phase. conserved the aspect of proteolytic maturation but evolved different mechanisms to achieve it. Our recent studies in human cells have revealed important links between HCF-1 and the E2F family of cell cycle regulators. E2F tran- Using worms, we have investigated the role of HCF proteins in animal scriptional regulators control human-cell proliferation by repressing development by characterizing the effects of loss of the HCF-1 homo- and activating the transcription of genes required for cell-cycle pro- log in C. elegans, called Ce HCF-1. Two large worm hcf-1 deletion gression, particularly the S phase. E2F proteins repress transcription mutants are viable but display reduced fertility. Loss of Ce HCF-1 in association with retinoblastoma pocket proteins but less has been protein at lower temperatures (e.g., 12°C) leads to a high incidence known about how they activate transcription. We have shown that of embryonic lethality and early embryonic mitotic and cytokinet- human HCF-1 associates with both activator (E2F 1 and E2F3a) and ic defects reminiscent of mammalian cell-division defects upon loss repressor (E2F4) E2F proteins, properties that are conserved among of mammalian HCF-1 function. Even when viable, however, at nor- their respective homologs in insect cells. Human HCF-1–E2F interac- mal temperature, mutant embryos display reduced levels of phos- Winship Herr received his PhD from Harvard University in 1982 tions are versatile: Their associations and binding to E2F-responsive pho-histone H3 serine 10 (H3S10P), a modification implicated in for studies on recombinant retroviruses in leukemogenic mice with promoters vary through the cell cycle, and HCF-1 displays co-activa- both transcriptional and mitotic regulation. Mammalian cells with Walter Gilbert. After postdoctoral studies with Frederick Sanger in tor properties when bound to the E2F1 activator and co-repressor defective HCF-1 also display defects in mitotic H3S10P status. These Cambridge England and Joe Sambrook at Cold Spring Harbor Labo- properties when bound to the E2F4 repressor. During the G1-to-S results suggest that HCF-1 proteins possess conserved roles in the ratory, he joined the Cold Spring Harbor Laboratory faculty in 1984. phase transition, HCF-1 recruits the MLL and Set-1 histone H3 lysine regulation of cell division and mitotic histone modification. There he served as assistant director of the Laboratory from 1994-2002 4 methyltransferases to E2F responsive promoters, and induces his- and from 1998-2004 was the founding dean of the Watson School of tone methylation and transcriptional activation. These results sug- Biological Sciences, a doctoral degree-granting school. He arrived at gest that HCF-1 induces cell-cycle-specific transcriptional activation the CIG in September 2004. Professor Herr was elected member of by E2F proteins to promote cell proliferation. the European Molecular Biology Organization (EMBO) in 2008.

18 CIG 2007/2008 Group members Publications Funding Collaborations

Group leader Apprentice technician research articles Swiss National Science M. Bogyo Winship Herr Bartosz Wierzbicki* Capotosti F, Hsieh JJ, Foundation (SNSF) Stanford University School [email protected] Herr W (2007) Independent Basic of Medicine, USA Editorial assistants Species selectivity of mixed- Research Grant A. Busturia Postdoctoral fellows “genes & development” lineage leukemia/trithorax Oncosuisse/Ligue Suisse Universidad Autonoma Pei-Jiun Chen Muriel Delestre-Cartier* and HCF proteolytic matura- contre le Cancer de Madrid, Spain Christina Hertel Laurence Flückiger tion pathways. Mol Cell Biol Independent Basic M. Delorenzi and F. Schütz Virginie Horn Helen Lennox 27:7063-7072 Research Grant Swiss Institute of Bioinformatics Joëlle Michaud Lee S, Horn V, Julien E, Ministerio de Educacion (SIB), Lausanne, Switzerland Sara Rodriguez-Jato Secretary Liu Y, Wysocka J, Bowerman y Ciencia (Spain) M. Hengartner Shweta Tyagi Nathalie Clerc B, Hengartner MO, Herr W Postdoctoral fellowship to University of Zurich, Switzerland [email protected] (2007) S. Rodriguez-Jato J. Hsieh PhD students Epigenetic Rrgulation of histone European Molecular Biology Washington University, Monica Albarca *left the group H3 serine 10 phosphorylation Organization (EMBO) St. Louis, USA Francesca Capotosti 1 part-time status by HCF-1 proteins in C. Long term fellowship to S. Tyagi Sophie Guernier Elegans and mammalian cells. J. Tamkun Federation of European PLoS ONE 2:e1213 University of California, Masters students Biochemical Societies (FEBS) Santa Cruz, USA Tyagi S, Chabes AL, Postdoctoral fellowship to Cynthia Dayer* S. Verhelst Wysocka J, Herr W (2007) C. Hertel Diego Gonzalez E2F activation of S phase Technische Universität München, Roche Research Foundation promoters via association with Germany summer Students/ • PhD Fellowship to F. Capostoti HCF-1 and the MLL family of trainees • Postoctoral fellowship to histone H3K4 methyltransferases. V. Horn Frédéric Laurent* Mol Cell 27:107-119 Ana Tufegjzic* Nicolai Wohns

Bioinformatician Viviane Praz

Technicians Jean-Paul Abbuehl* Philippe L’Hôte1 Fabienne Messerli Cynthia Zimmermann1

19 Research

Henrik Kaessmann Mammalian evolutionary genomics Associate Professor

The research of my group has focused on the origin and evolution of key features of mammals – lactation and placentation – and the of new genes that emerged from duplicate gene copies in primates associated loss of egg yolk nourishment of the young. We found and other mammals. We have been particularly interested in the ori- that egg yolk genes were progressively lost in mammals due to the gin of new genes by retroposition (also termed retroduplication), emergence of alternative nourishment resources for the young: lac- a mechanism that creates intronless duplicate gene copies in new tation (we found that key milk genes – caseins – emerged in the genomic positions through the reverse transcription of mRNAs from common ancestor of all mammals) and the placenta. parental source genes. Finally, in collaboration with Dr. Amalio Telenti (Institute of Microbiol- In the past two years, we have uncovered a novel mechanism underly- ogy, and University Hospital (CHUV), Lausanne), we completed several ing the emergence of new gene functions through a unique combina- projects pertaining to the evolution of antiviral restriction in primates. tion of evolutionary analyses and genomics/cell biology experiments. We found that proteins encoded by newly emerged genes can obtain new functional roles during evolution through changes of their local- ization in the cell, a process that we termed subcellular adaptation. We also followed up on our original work pertaining to the out– of–X movement of genes. In this study, we established the reason for the excess of new retrogenes originating from X–linked paren- tal genes: autosomal retrogenes substitute for the silencing of their X–linked parents during the transcriptional silencing of sex chromo- somes during meiosis. Moreover, by dating the onset of the out–of– X movement, we established that our sex chromosomes originated late in the common ancestor of placental mammals and marsupials – rather than in the ancestor common to all mammals – and are thus much younger than previously thought. In the framework of another line of research, we completed a major study performed in collaboration with the group of Prof. Alexandre Reymond pertaining to copy number variation (CNV) of genes with- Birth and rapid, selectively driven in a species/population due to the duplication or deletion of genes. subcellular adaptation In this study, we established (using the mouse as a model) that CNV of a hominoid-specific CDC 14B protein. shapes tissue transcriptomes in various ways. We showed that the Henrik Kaessmann received his PhD in 2001 from the University expression of genes both within and in the vicinity of CNV regions of Leipzig after working on the genetic diversity of humans and are affected by copy number changes. The extent of CNV-induced the great apes in the laboratory of Dr. S. Pääbo at the University of expression change depends on the spatial expression pattern of Munich and subsequently at the MPI for Evolutionary Anthropology, genes. For example, genes expressed in the brain are less affected Leipzig. He obtained his postdoctoral training with Dr. Wen-Hsiung Li by copy number changes, presumably due to more efficient regu- in the Dpt of Ecology and Evolution at the University of Chicago, latory feedback loops. Together with the observation that brain- where he worked on the origin of human genes and gene structures. expressed genes are underrepresented in CNV region, our results In 2003 he joined the CIG as an Assistant Professor. He was appointed suggest strong selective constraint on gene expression changes in Associate Professor (with tenure) in 2007. Since 2005, he has been the brain. an EMBO Young Investigator. He was awarded the Basic Life Science Award by the Faculty of Biology and Medicine, UNIL in 2008 for his In parallel to these lines of research, my group has pursued other outstanding contributions to Basic Life Sciences research at the UNIL. projects regarding the origin of mammal–specific phenotypes. For example, we performed a study regarding the evolutionary origin

20 CIG 2007/2008 Group members Publications Funding Collaborations

Group leader research articles Rosso L, Marques A, Swiss National Science B. Jégou Henrik Kaessmann Brawand D, *Wahli W, Reichert A, Kaessmann H (2008) Foundation (SNSF) University of Rennes, France [email protected] *Kaessmann H (2008) Mitochondrial targeting adapta- Independent Basic Research S. Pääbo Loss of egg yolk genes in mam- tion of the hominoid-specific Grant MPI for Evolutionary Postdoctoral fellows mals and the origin of lactation glutamate dehydrogenase driven Faculty of Biology and Anthropology, Leipzig, Germany by positive Darwinian selection. Jean-Vincent Chamary* and placentation. PLoS Biol Medicine (FBM), UNIL A. Reymond PLoS Genet 4:e1000150 Marie Fablet* 6:e63. Interdisciplinary research project, UNIL, Lausanne, Switzerland Maxwelll Ingman* Rosso L, Marques AC, awarded in 2005 Goldschmidt V, Ciuffi A, A. Telenti Lia Rosso Weier M, Lambert N, Ortiz M, Brawand D, European Commission (FP6) UNIL, Lausanne, Switzerland Nicolas Vinckenbosch** Munoz M, *Kaessmann H, Lambot M-A, Vanderhaeghen P, Project “Molecular Evolution of *Telenti A (2008) Kaessmann H (2008) Human Cognition“ PhD students Birth and Rapid Subcellular Ad- Antiretroviral activity of European Molecular Biology aptation of a Hominoid-Specific David Brawand ancestral TRIM5alpha. J Virol Organization (EMBO) CDC14 Protein. PLoS Biol 6:e140 Philippe Julien 82:2089-2096 • Young Investigator Award Ana Marques* Marques AC, Vinckenbosh Parmley JL, Urrutia AO, 2005 Lukasz Potrzebowski N, Brawand D, Kaessmann H Potrzebowski L, • Postdoctoral fellowship to Magali Soumillon (2008) Kaessmann H, Hurst LD (2007) J.M. Chamary Nicolas Vinckenbosch** Splicing and the evolution of Functional diversification of du- Roche Research Foundation proteins in mammals. PLoS Biol Masters students plicate genes through subcellular PhD fellowship to D. Brawand adaptation of encoded proteins. 5:e14 Lionel Maquelin* Genome Biol 9:R54 Sophie Nicod *joint senior authors Ortiz M, Kaessmann H, Zhang K, Technician Bashirova A, Carrington M, Quintana-Murci L, Telenti A Manuela Weier (2008) Apprentice technician The evolutionary history of the CD209 (DC-SIGN) family in hu- Philippe Kirchner* mans and non-human primates. Secretary Genes Immun 9:483-492 Potrzebowski L, Vinckenbosch N, Annick Crevoisier Marques AC, Chalmel F, [email protected] Jegou B, Kaessmann H (2008) *left the group Chromosomal Gene Movements Reflect the Recent Origin and **changed function Biology of Therian Sex Chromo- somes. PLoS Biol 6:e80 Rosso L, Keller L, Kaessmann H, Hammond RL (2008) Mating system and avpr1a promoter variation in primates. Biol Lett 4:375-378

21 Research

Sophie Martin Molecular mechanisms of cell polarization Professeur boursier SNSF

Polarity is crucial for cell function both during development and in Formin-dependent cell polarization differentiated cells. Cell polarity underlies the asymmetric division of stem cells to generate cell diversity and the function of differenti- Formins are key actin organizers that nucleate linear actin filaments. ated cells, such as neurons, epithelial or immune cells. In prolifer- Formins are essential for cell polarization in vegetative cells as they ating cells, cell polarization is tightly linked with cell cycle controls. assemble a polarized network of actin cables that allows the delivery of Indeed, loss of cell polarity has been associated not only with diseas- myosin-driven cargoes to sites of polarized cell growth. These cargoes es affecting specific tissues or organs, but also with cancer, where include membrane material and cell wall remodeling components it may contribute to uncontrolled proliferation. Thus understanding essential for polarized cell growth. Yeast cells also show prominent how a cell acquires and maintains polarity is a fundamental question polarization during the mating process, when two cells of opposite in cell biology. mating type extend cellular projections towards each other. We are currently investigating formin regulation during polarized cell growth. Our research aims to address how a cell acquires and maintains cell polarity and how this process is linked with cell proliferation. We Connections between polarization and use the fission yeast, Schizosaccharomyces pombe, as model system proliferation because it affords powerful genetic, biochemical and live-cell imag- ing tools. Fission yeast has a very small genome, encoding about Cell polarization is intimately linked to cell cycle changes. For 5000 genes, two thirds of which show direct homology with mam- instance, it has been proposed that loss of cell polarity influences cell malian genes. This organism has been successfully used over the last proliferation and contributes to tumour formation. We have focused 30 years to unravel fundamental mechanisms of cell proliferation our investigations on a well-studied regulator of cell morphogenesis, and morphogenesis. We focus on three major areas of research: the DYRK kinase pom1p, and uncovered a novel function for pom1p as an inhibitor of cell cycle progression. Pom1p forms gradients from Microtubule-dependent cell polarization cell ends. As cells grow in length during interphase, the pom1p gra- dients get further apart, lowering the concentration of pom1p at the The cytoskeleton – microtubules and actin filaments – is essential for cell middle in longer cells. We found that pom1p negatively regu- cell polarization. In rod-shaped fission yeast cells, microtubules are lates the SAD kinase cdr2p, a cell cycle activator itself localized at organized in a dynamic network aligned with the length of the cell the cell equator throughout interphase. Our data suggest a model in and serve to transport polarity determinants towards the extremities which overlap between pom1p and cdr2p at the middle of short cells of the cell. Microtubules provide positional information for growth leads to mitotic delay while pom1p levels are no longer sufficient at cell extremities and cells with anomalies in their microtubule net- at the middle of long cells to inhibit cdr2p, thus allowing entry into work grow at ectopic locations. The actin cytoskeleton is organized mitosis. Gradients of pom1p thus provide a novel cell-intrinsic mea- at the cell extremities and essential for polarized growth. We had sure of cell length to ensure that sufficient length is attained before previously demonstrated that a microtubule-associated protein, division. The high conservation of cell cycle regulators and cell polar- tea4p, binds an actin nucleator of the formin family, for3p, thereby ization mechanisms across evolution suggests that lessons learned Sophie Martin earned her Diploma in 1999 from the UNIL for her directly linking positional information provided by microtubules to from yeast will be applicable to mammalian cells. study of chromatin organization in the laboratory of Dr Susan Gasser actin assembly. We have now generated point mutations in tea4p at the Swiss Institute for Experimental Cancer Research (ISREC). She to investigate its mode of localization and regulation. Our ongoing then joined the group of Dr Daniel St Johnston at the Wellcome/CR UK investigations suggest that tea4p may integrate phosphorylation Gurdon Institute to study the molecular mechanisms of cell polariza- and de-phosphorylation events to control cell polarization. tion and mRNA localization using Drosophila as model system and received her PhD in 2003 from the University of Cambridge. She obtained postdoctoral training in the laboratory of Dr Fred Chang at Columbia University in New York, studying cell polarization and the cytoskeleton in the fission yeast. She joined the CIG as a Swiss National Science Foundation Professor in September 2007.

22 CIG 2007/2008 Group members Publications Funding and Collaborations

Group leader research article Funding Sophie Martin Martin SG, Rincon SA, Basu R, Swiss National Science [email protected] Perez P, Chang F (2007) Foundation (SNSF) Regulation of the formin for3p by SNSF professorship Postdoctoral fellows cdc42p and bud6p. Mol Biol Cell Human Frontier Science Felipe Bendezú 18:4155-4167 Program (HFSP) Yanfang Ye Career Development Award 2008 PhD student Roche Research Foundation Kyriakos Kokkoris PhD Fellowship to K. Kokkoris summer Students Collaboration Cylia Rochat* Zhou Zhou* P. Perez University of Salamanca, Spain Technician Martine Berthelot-Grosjean

Secretary Nathalie Clerc [email protected]

*left the group

23 Research

Liliane Michalik Transcriptional control of tissue repair and angiogenesis Maître d’Enseignement et de Recherche

The vasculature is required to ensure blood and nutrient supply to the developing organs in the embryo, for organ and body growth after birth, and for organ repair in the adult. Because of this key functions, the vasculature and the heart are the first organ sys- tems to be functional in vertebrate development. The nuclear hor- mone receptors PPARs were initially identified as regulators of ener- gy metabolism and inflammation. Interestingly, they were recently reported as modulators of blood vessel formation, although the mechanisms remain unclear. We are interested in the functions of PPARs in the development of blood vessels during embryogenesis, adult skin repair and skin tumor growth. The skin is the barrier that protects the organism from various insults. Due to its peripheral localization, it is prone to be damaged, for instance by mechanical injury or UV radiations. Healing of cutane- ous wounds proceeds via a well-tuned pattern of events that include inflammation, re-epithelialization, and matrix and tissue remodeling. We have observed that inflammatory molecules released immediate- ly after the injury increase the expression of PPARbeta and trigger the production of endogenous PPARbeta ligands. Once expressed at high levels and activated, PPARbeta activates a major cellular sur- vival pathway, which protects keratinocytes from death at the site of injury. Re-epithelialization depends on directional sensing and migration of keratinocytes, two processes that are impaired in PPAR- beta-null mice. We found that the activation of PPARbeta amplifies a cellular internal signal, involving localized increase in the PIP3/PIP2 ratio, which is required for cellular directional sensing and activa- tion of several effectors involved in cell polarization and pseudopo- dia extension. These processes are impaired in PPARbeta-null kerati- nocytes due to a reduced activity of the PI3K/Akt1 signaling cascade and its effectors involved in actin cytoskeleton plasticity and integrin recycling. Consistently, early wound biopsies of PPARbeta-null mice reveal delayed and uncoordinated migratory fronts at the wound Liliane Michalik received her PhD from the University Louis Pasteur edge demonstrating a defect in directional sensing and migration of Strasbourg in 1993, for work on microtubule-associated proteins in in vivo. In addition to re-epithelialization of the epidermis, these cell the group of Jean-François Launay, INSERM. In 1994, she joined the functions and molecular mechanisms are also involved in the devel- group of Walter Wahli at UNIL for her post-doctoral training, during opment of tumors and in angiogenesis. We currently explore the which she initiated a research project aimed at elucidating the roles of roles of PPARs as transcriptional regulators of the nuclear hormone receptors PPARs in skin homeostasis and repair. Between 1996 and 2002, she persued her research in the same field i) blood vessels formation during embryogenesis in the Xenopus as Maître Assistant, then Maître d’Enseignement et de Recherche at tadpole and the mouse embryo, UNIL. She arrived at the Center for Integrative Genomics in 2003 as ii) angiogenesis during skin repair Maître d’Enseignement et de Recherche, and is MER-privat docent since 2008. iii) UVB-induced skin tumor growth.

24 CIG 2007/2008 Group members Publications Funding and Collaborations

Group leader research articles reviews Funding Liliane Michalik Rodriguez-Calvo R, Serrano **Michalik L, **Wahli W Swiss National Science [email protected] L, Coll T, Moullan N, Sanchez (2008) Foundation (SNSF) RM, Merlos M, Palomer X, PPARs Mediate Lipid Signaling in Independent Basic PhD students Laguna JC, Michalik L, Wahli Inflammation and Cancer. PPAR Research Grant Raphaël Terrier W, Vazquez-Carrera M (2008) Res 2008:134059. Marta Wawrzyniak Activation of peroxisome prolif- Collaborations **Michalik L, **Wahli W erator-activated receptor beta/ D. Dombrowicz Masters Students (2007) delta inhibits lipopolysaccharide- Institut Pasteur de Lille, France David Barras* induced cytokine production in Peroxisome proliferator-activated D. Hohl Michaël Baruchet adipocytes by lowering nuclear receptors (PPARs) in skin health, University Hospital (CHUV), Nicolas Damont* factor-kappaB activity via extra- repair and disease. Biochim Lausanne, Switzerland Frédéric Laurent* cellular signal-related kinase 1/2. Biophys Acta 1771:991-998 Aurélie Righetti Diabetes 57:2149-2157 Michalik L, Wahli W (2007) O. Michielin and V. Zoete Guiding ligands to nuclear recep- *Michalik L, *Zoete V, Krey Swiss Institute of Bioinformatics tors. Cell 129:649-651 Technicians G, Grosdidier A, Gelman L, (SIB), Lausanne, Switzerland Cécile Duléry* Chodanowski P, Feige JN, Michalik L, Wahli W (2007) T. Odorisio Christiane Freymond Desvergne B, ***Wahli W, Roles of the peroxisome prolifer- Instituto Dermopatico del Maude Husson ***Michielin O (2007) ators-activated receptor (PPAR) l’Immacolata, IDI-IRCCS, Hélène Mottaz Combined simulation and alpha and beta/delta in skin Rome, Italie mutagenesis analyses reveal wound healing. International M. Swartz Secretary the involvement of key residues Congress Series 1302:45-52 EPFL, Lausanne, Switzerland for peroxisome proliferator- Marlène Petit S. Werner activated receptor alpha helix 12 book chapter [email protected] ETHZ, Zurich, Switzerland dynamic behavior. J Biol Chem Michalik L, Wahli W (2008) *left the group 282:9666-9677. Tissue repair and cancer control Tan NS, Icre G, Montagner through PPARs and their coregu- A, Bordier-ten-Heggeler B, lators. In: Nuclear Receptors Co- Wahli W, Michalik L (2007) regulators and Human Disease. The nuclear hormone receptor Edited by Kumar BOMaR. World peroxisome proliferator-activated Scientific Publishing, London receptor beta/delta potentiates Singapore; 409-440 cell chemotactism, polarization, and migration. Mol Cell Biol *both authors contributed equally to this work 27:7161-7175 **joint corresponding authors

***joint senior authors

25 Research

Alexandre Reymond Genome structure and expression Associate Professor

Copy Number Variant two and three copies of the same CNV in an otherwise identical genomic background. A fourth strain (Dp(11)17/Df(11)17) obtained A fundamental question in current biomedical research is to estab- by mating the Dp(11)17/+ and Df(11)17/+ animals allows to generate lish a link between genomic variation and phenotypic differences, mice with two copies of that same CNV in cis, while they are in trans which encompasses both the seemingly neutral polymorphic varia- in +/+ animals. tion, as well as the pathological variation that causes or predis- poses to disease. In addition to the millions of individual base-pair Preliminary studies of the hippocampus transcriptome of PTLS mod- changes that distinguish any two unrelated copies of our genome, els and normal littermates showed that a highly significant propen- recent reports have described large numbers of copy number vari- sity of the most differentially expressed transcripts are mapping to able regions (CNVs). Much effort has been put into the identification the engineered SMS/PTLS interval. Interestingly, a statistically signifi- and mapping of these regions in humans and a number of model cant overrepresentation of the genes mapping to the flanks of the organisms, but a comprehensive understanding of their phenotypic engineered interval was also found in the top-ranked differentially effects is only beginning to emerge. expressed genes, confirming the results described above. But how may changes in copy number of CNV regions alter the expression To assess the functional impact of CNVs at the genome-wide scale of genes in their vicinity? Different CNV-induced mechanisms that we have undertaken a large-scale CNV study using the mouse as a include the physical dissociation of the transcription unit from its model organism. We have generated an extensive map of CNV in cis-acting regulators, modification of transcriptional control through wild mice and classical inbred strains. Copy number variable regions alteration of chromatin structure, and modification of the position- cover ~11% of their autosomal genome. Genome-wide expres- ing of chromatin within the nucleus and/or within a chromosome sion data from different major organs not only reveal that expres- territory of a genomic region might play a role, both individually or sion levels of genes within CNVs tend to correlate with copy number in combination. Copy number changes might also influence gene changes, but also that CNVs influence the expression of genes in expression through perturbation of transcript structure. their vicinity - an effect that extends up to half a megabase. Notably, genes within CNVs show lower expression levels and more specif- Balanced rearrangement ic spatial expression patterns than genes mapping elsewhere in the genome. Furthermore, our analyses reveal differential constraint on A third type of variation comprises the balanced chromosomal rear- copy number changes of genes expressed in different tissues. In par- rangements, such as reciprocal translocations and inversions, which ticular, dosage alterations of brain-expressed genes are less frequent elicit no gain or loss of genetic material. Balanced rearrangements than those of other genes and are buffered by tighter transcriptional occur in approximately 1 in 500 individuals in the general population regulation. Thus, we provide initial evidence that CNVs shape tis- and recent studies have identified hundreds of polymorphic inver- sue transcriptomes on a global scale and thus represent a substantial sions. We will study the effect of balanced chromosomal rearrange- source for within-species phenotypic variation. ments on gene expression by comparing the transcriptomes of cell Alexandre Reymond carried out his thesis in the laboratory of lines from control and t(11;22)(q23;q11) individuals. This transloca- Dr. Viesturs Simanis at the Swiss Institute for Experimental Cancer Mechanisms at play tion between chromosomes 11 and 22 is the only recurrent constitu- tional non-Robertsonian translocation in humans. Research (ISREC) and received his PhD from the UNIL in 1993. After The functional impact of modifying the copy number of a given copy completion of his postdoctoral training with Dr Roger Brent in the number variation remains unstudied at a genome-wide scale. Such Department of Molecular Biology, Massachusetts General Hospital a global assessment is achievable nowadays using the mouse as a and in the Department of Genetics, Harvard Medical School in Boston, model organism. Mouse models of the Smith-Magenis (SMS) and he moved to the Telethon Institute of Genetics and Medicine (TIGEM) Potocki-Lupski (PTLS) syndromes carry a deletion at band MMU11B2 in Milan in 1998 to lead a research group. He joined in 2000 the (strain Df(11)17)/+) and its reciprocal duplication (Dp(11)17/+), respec- Department of Genetic Medicine and Development, University of tively. These heterozygous mice show phenotypic features similar to Geneva Medical School. He moved to the Center for Integrative those identified in human SMS and PTLS patients. These models and Genomics in October 2004 and became an Associate Professor in their normal littermates (+/+) allow to study the influence of one, February 2009.

26 CIG 2007/2008 Group members Publications Funding and Collaborations

Group leader Vidal M, Salehi-Ashtiani K, Henrichsen CN, Holroyd N, Denoeud F, Jones P, Kerrien S, Funding E. Birney Alexandre Reymond Antonarakis SE, Gingeras TR, Dickson MC, Taylor R, Hance Z, Orchard S, Antonarakis SE, Swiss National Science EBI, Hinxton, UK [email protected] Guigo R (2008) Foissac S, Myers RM, Rogers J, Reymond A, Birney E, Brunak S, Foundation (SNSF) J. Dekker Efficient targeted transcript discov- Hubbard T, Harrow J, Guigo R, Casadio R, Guigo R, Harrow J, • Independent Basic University of Massachusetts, Postdoctoral fellows ery via array-based normalization Gingeras TR, Antonarakis SE, Hermjakob H, Jones DT, Research Grant Worcester, USA of RACE libraries. Nat Methods Reymond A (2007) Lengauer T, C AO, Patthy L, Emilie Aït Yahya Graison • Marie Heim Vögtlin (MHV) E.T. Dermitzakis, J. Harrow 5:629-635 Prominent use of distal 5’ transcrip- Thornton JM, Tramontano A, Gérard Didelot Postdoctoral subsidy to and T. Hubbard tion start sites and discovery of a Valencia A (2007) Nele Gheldof Marshall CR, Young EJ, N. Gheldof Wellcome Trust Sanger Institute, Louise Harewood large number of additional exons The implications of alternative Pani AM, Freckmann ML, European Commission (FP6) Cambridge, UK Guénola Ricard Lacassie Y, Howald C, in ENCODE regions. Genome Res splicing in the ENCODE protein Project AnEUploidy C.G. Elsik Fitzgerald KK, Peippo M, 17:746-759 complement. Proc Natl Acad Sci Georgetown University, PhD students Morris CA, Shane K, Priolo M, ENCODE Consortium (2007) U S A 104:5495-5500 National Institutes of Health Washington, USA Evelyne Chaignat Morimoto M, Kondo I, Identification and analysis of Washietl S, Pedersen JS, (NIH), USA • Charlotte Henrichsen Manguoglu E, Berker-Karauzum S, functional elements in 1% of the Korbel JO, Stocsits C, Gruber AR, Project “Integrated human E. Eyras Cédric Howald Edery P, Hobart HH, Mervis CB, human genome by the ENCODE Hackermuller J, Hertel J, genome annotation: Universitat Pompeu Fabra, Robert Witwicki Zuffardi O, Reymond A, pilot project. Nature 447:799-816 Lindemeyer M, Reiche K, Tanzer A, generation of a reference Barcelona, Spain gene set“ Kaplan P, Tassabehji M, Gregg RG, Ucla C, Wyss C, Antonarakis SE, T. E. Gingeras Technician Lyle R, Prandini P, Osoegawa K, • Project: ”Comprehensive Scherer SW, Osborne LR (2008) ten Hallers B, Humphray S, Denoeud F, Lagarde J, Drenkow J, Cold Spring Harbor Lab, USA Jacqueline Chrast characterization and Infantile spasms is associated with Zhu B, Eyras E, Castelo R, Bird CP, Kapranov P, Gingeras TR, Guigo R, R. Guigo deletion of the MAGI2 gene on Snyder M, Gerstein MB, classification of the human Secretary Gagos S, Scott C, Cox A, transcriptome” Centre de Regulació Genomica, chromosome 7q11.23-q21.11. Deutsch S, Ucla C, Cruts M, Reymond A, Hofacker IL, Barcelona, Spain Annick Crevoisier Am J Hum Genet 83:106-111 Dahoun S, She X, Bena F, Wang SY, Stadler PF (2007) Fondation Désirée & Niels Yde [email protected] Structured RNAs in the ENCODE Fondation Jérôme Lejeune H. Kaessmann Micale L, Fusco C, Augello B, Van Broeckhoven C, Eichler EE, UNIL, Lausanne, Switzerland Napolitano LM, Dermitzakis ET, Guigo R, Rogers J, de Jong PJ, selected regions of the human Novartis Foundation research articles Meroni G, Merla G, Reymond A Reymond A, Antonarakis SE genome. Genome Res 17:852-864 Roche Research Foundation J. Lupski (2008) (2007) Zheng D, Frankish A, Baertsch R, Postdoctoral fellowship to Baylor College of Medicine, Attanasio C, Reymond A, Williams-Beuren syndrome TRIM50 Islands of euchromatin-like Kapranov P, Reymond A, G. Didelot Houston, USA Humbert R, Lyle R, Kuehn MS, encodes an E3 ubiquitin ligase. sequence and expressed polymor- Choo SW, Lu Y, Denoeud F, Fondation Telethon Action G. Merla Neph S, Sabo PJ, Goldy J, Eur J Hum Genet 16:1038-1049 phic sequences within the short Antonarakis SE, Snyder M, Suisse IRCCS “Casa Sollievo della Weaver M, Lee K, Haydock A, arm of human chromosome 21. Ruan Y, Wei CL, Gingeras TR, Faculty of Biology and Sofferenza”, Dermitzakis ET, Dorschner MO, Molina J, Carmona-Mora P, Genome Res 17:1690-1696 Guigo R, Harrow J, Gerstein MB Medicine (FBM), UNIL San Giovanni Rotondo, Italy Antonarakis SE, Chrast J, Krall PM, Canales CP, (2007) Ph.D. fellowship to R. Witwicki Stamatoyannopoulos JA (2008) Lupski JR, Reymond A, Walz K Tress ML, Martelli PL, Frankish A, L. Osborne Pseudogenes in the ENCODE Assaying the regulatory potential of (2008) Reeves GA, Wesselink JJ, Yeats C, University of Toronto, Canada regions: consensus annotation, Collaborations mammalian conserved non-coding Abnormal social behaviors and Olason PL, Albrecht M, Hegyi H, L. Pérez Jurado analysis of transcription, and sequences in human cells. Genome altered gene expression rates Giorgetti A, Raimondo D, S. E. Antonarakis Universitat Pompeu Fabra, evolution. Genome Res 17:839-851 Biol 9:R168 in a mouse model for Potocki- Lagarde J, Laskowski RA, University of Geneva, Switzerland Barcelona, Spain Lupski syndrome. Hum Mol Genet Lopez G, Sadowski MI, review A. Ballabio K. Walz Djebali S, Kapranov P, Foissac S, 17:2486-2495 Watson JD, Fariselli P, Rossi I, Telethon Institute of Genetics Centro de Estudios Científicos, Lagarde J, Reymond A, Ucla C, Nagy A, Kai W, Storling Z, Reymond A, Henrichsen CN, Denoeud F, Kapranov P, Ucla C, and Medicine, Naples, Italy CECS, Valdivia, Chile Wyss C, Drenkow J, Dumais E, Orsini M, Assenov Y, Harewood L, Merla G (2007) Frankish A, Castelo R, Drenkow J, W.A. Bickmore, Murray RR, Lin C, Szeto D, Blankenburg H, Huthmacher C, Side effects of genome Denoeud F, Calvo M, Frankish A, Lagarde J, Alioto T, Manzano C, MRC, Edinburgh, UK Chrast J, Dike S, Wyss C, Ramirez F, Schlicker A, structural changes. Curr Opin Harrow J, Makrythanasis P, Genet Dev 17:381-386

27 Research

Andrzej Stasiak Functional transitions of DNA structure Maître d’Enseignement et de Recherche

Our group is interested in two main subjects: to understand how the scaling behaviour of global curvature and global torsion depends on the knot type of the polymer chains with 1. Topology and biophysics of DNA and of polymers in general, increasing length. For more details, see: Total curvature and total tor- 2. Mechanism of action of proteins involved in DNA recombination sion of knotted polymers. Macromolecules, 40, 3860-3867, 2007. and DNA repair. Another collaboration project in the field of biophysics of polymers In the field of DNA topology one of central questions pursued in concerned investigation of basic shapes adopted by cylindrical tubes many laboratories is how DNA topoisomerases keep the level of that locally attract each other. We observed that most of known bio- DNA knotting much below the level that would have resulted from logical structures can be reproduced and explained using this very random intersegmental passages. One of the considered hypotheti- simple tube model. See: Structural motifs of biomolecules. PNAS, cal mechanisms proposed that topoisomerases may act preferential- 104, 17283-17286, 2007. ly at DNA-DNA juxtapositions where two independent DNA regions The second leading subject of our research proposal concerned are interhooked with each other. We have tested this mechanism investigation of mechanism of action of various proteins involved in by numerical simulations and demonstrated that selection of inter- the process of DNA recombination and DNA repair. hooked juxtapositions could indeed provide a mechanism assuring that steady state knotting level within living cells is orders of magni- In a collaboration project with the group of Prof. A. Constantinou tude lower than this that would heave resulted from random inter- (UNIL) aimed to understand the action and function of FANCM pro- segmental passages. For more details, see: Burnier Y., Weber C., tein. This human protein is required for DNA repair after various Flammini A. & Stasiak A. Local selection rules that can determine DNA damages including DNA crosslinking. Patients with defective specific pathways of DNA unknotting by type II DNA topoisomer- FANCM gene suffer from Fanconi anaemia. Our electron microscopy ases. NAR, 35: 5223 – 5231, 2007. images revealed that FANCM protein preferentially binds to point of strand exchange in Holliday junctions. These images complemented Continuing our efforts directed toward understanding how DNA biochemical analysis performed in the laboratory of A. Constantinou topoisomerases avoid DNA knotting in bacterial cells we investigated and strongly indicated that the FANCM protein promotes branch the effect of DNA supercoiling on DNA knotting and have revealed migration by specific interaction with the strand exchange region that supercoiling provides the free energy gradient that opposes in Holliday junctions. For more details, see: FANCM can promote DNA knotting. Burnier, Y., Dorier, J. & Stasiak, A. DNA supercoiling branch migration of Holliday junctions and regression of replication inhibits DNA knotting. NAR, 36: 4956-4963, 2008. forks. Molecular Cell, 29, 141-148, 2008. Consideration of DNA knots and DNA topoisomerases provided a Continuing our productive collaboration with the group of J.-Y. Masson motivation for the development of a software that could be used (Canada) we participated in two projects intended to understand to find out which pairs of DNA knots can be converted into each functions of proteins that stimulate and participate in Dmc1 and other by one intersegmental passage mediated by type II DNA topi- Rad51-mediated DNA recombination and DNA repair. For more somerases or that could tell for example how many topo II mediated details, see: Fission yeast and mouse Hop2-Mnd1 stimulate Dmc1 passages are needed to convert a given knot into another one. The and Rad51 recombinases. NAR, 35, 2719-2733, 2007 and A glycine- software development project was done with external collaborators arginine domain in control of the human MRE11 DNA repair protein. (Isabel Darcy, USA and Rob Scharein, Canada). To make our soft- Mol. Cell. Biol., 28, 3058-3069, 2008. Andrzej Stasiak received his PhD in 1981 from the Institute of ware broadly known and accessible to interested biologists we have Biochemistry and Biophysics of Polish Academy of Sciences in Warsaw. described it in a paper: Darcy I., Scharein R. & Stasiak A. 3D visual- From 1981 to 1989 he was a postdoctoral fellow and research asso- ization software to analyse topological outcomes of topoisomerase ciate in the laboratory of Theodor Koller at Institute for Cell Biology, reactions. NAR, 36, 3515-3521, 2008. ETHZ, Zurich, Switzerland. In 1989 he joined the Laboratory of Ultrastructuaral Analysis directed by Jacques Dubochet at the UNIL. The effects of knotting on statistical mechanics of cyclic polymers is In 2007 he joined the Center for Integrative Genomics as Maître currently an active field of research. In a collaboration project involv- d’Enseignement et de Recherche (MER). ing several laboratories we have used numerical simulation approach

28 CIG 2007/2008 Group members Publications Funding and Collaborations

Group leader research articles Rawdon EJ, Dobay A, Kern J, Ploquin M, Petukhova GV, book chapters Funding Andrzej Stasiak Burnier Y, Dorier J, Stasiak A Millet K, Piatek M, Plunkett P, Morneau D, Dery U, Bransi A, Cerf C, Stasiak A (2007) Swiss National Science [email protected] (2008) Stasiak A (2008) Stasiak A, Camerini-Otero RD, Linear behaviour of the writhe Foundation (SNSF) DNA supercoiling inhibits DNA Scaling behavior and equilibrium Masson JY (2007) versus the number crossings Independent Basic PhD student knotting. Nucleic Acids Res lenghts of knotted polymers. Stimulation of fission yeast in rational knots and links. In: Research Grant Davide Demurtas 36:4956-4963 Macromolecules 41:4444-4451 and mouse Hop2-Mnd1 of the Topology in Molecular Biol- Dmc1 and Rad51 recombinases. Collaborations Darcy IK, Scharein RG, Banavar JR, Hoang TX, ogy. Edited by Monastyrsky MI. civilian service Maddocks JH, Maritan A, Nucleic Acids Res 35:2719-2733 Stasiak A (2008) Springer-Verlag, Berlin A. Constantinou Poletto C, Stasiak A, Plunkett P, Piatek M, Dobay A, Yannis Burnier* 3D visualization software to Heidelberg 111-125 UNIL, Lausanne, Switzerland Julien Dorier Trovato A (2007) Kern JC, Millet KC, Stasiak A, analyze topological outcomes of Flammini A, Stasiak A (2007) I. Darcy Guillaume Witz* Structural motifs of biomol- Rawdon EJ (2007) topoisomerase reactions. Nucleic Natural classification of knots. University of Iowa, Acids Res 36:3515-3521 ecules. Proc Natl Acad Sci U S A Total curvature and total torsion In: Knot theory for scientific Technician 104:17283-17286 of knotted polymers. Macromol- Iowa City, USA Dery U, Coulombe Y, objects. Edited by Kawauchi A. Alicja Z. Stasiak Burnier Y, Weber C, ecules 40:3860-3867 Osaka Municipal Universities Y. Diao Rodrigue A, Stasiak A, University of North Carolina, Richard S, Masson JY (2008) Flammini A, Stasiak A (2007) Press, Osaka. 293-306 Secretary Charlotte, USA A glycine-arginine domain in Local selection rules that can comment Marlène Petit control of the human MRE11 determine specific pathways of G. Dietler [email protected] DNA repair protein. Mol Cell Biol DNA unknotting by type II DNA Stasiak AZ, Stasiak A (2008) EPFL, Lausanne, Switzerland 28:3058-3069 topoisomerases. Nucleic Acids RecA-DNA complexes. J. Maddocks *left the group Res 35:5223-5231 CHEMTRACTS-Biochemistry and Gari K, Decaillet C, Stasiak AZ, EPFL, Lausanne, Switzerland Molecular Biology 21:399-405 Stasiak A, Constantinou A Diao Y, Stasiak A (2007) J.-Y. Masson (2008) Self-avoiding random walks and Laval University Cancer Research The Fanconi anemia protein Olber’s paradox. International Center, Québec, Canada Journal of Contemporary Math- FANCM can promote branch K. C. Millett ematical Sciences 2:445-449 migration of Holliday junctions University of California, and replication forks. Mol Cell Fierro-Fernandez M, Santa Barbara, USA 29:141-148 Hernandez P, Krimer DB, E. Rawdon Stasiak A, Schvartzman JB Ploquin M, Bransi A, Paquet ER, University of St. Paul, USA Stasiak AZ, Stasiak A, Yu X, (2007) J. B. Schvartzman Cieslinska AM, Egelman EH, Topological locking restrains rep- Centro de Investigaciones Moineau S, Masson JY (2008) lication fork reversal. Proc Natl Biológicas (CSIC), Functional and structural basis Acad Sci U S A 104:1500-1505 Madrid, Spain for a bacteriophage homolog Flammini A, Stasiak A (2007) of human RAD52. Curr Biol Natura classification of Knots. 18:1142-1146 Proc Roy Soc A 463:569-582 Rawdon E, Kern J, Piatek M, Plunkett P, Stasiak A, Millet K (2008) The effect of knotting on the shape of polymers. Macromol- ecules 41:8281-8287

29 Research

Mehdi Tafti Genetics of sleep and the sleep EEG Associate Professor

Based on available literature there is no doubt that many aspects of Genetic s of sleep disorders sleep are under a genetic control in both humans and animal mod- els. These include not only the amount and the distribution of sleep Many sleep disorders run in families but their genetic bases are poorly but also very specific electroencephalographic (EEG) features of understood. Our laboratory is specialized in the genetics of narcolepsy sleep and wakefulness. By using the inbred mouse as a genetic tool, and sleepwalking. We perform family – and population – based stud- we have been able to demonstrate that sleep as a quantitative trait ies using linkage, candidate gene, and genome-wide associations. is amenable to quantitative trait loci analysis (QTL). Although many We have also initiated a new Center for Investigation and Research genes with small effects might affect the amount and the distribu- in Sleep (CIRS) in collaboration with the Department of Medicine of tion of sleep, some aspects such as the daily amount of paradoxical the University Hospital (CHUV), Lausanne, where we plan to conduct sleep may be under a major gene control. We have localized such a sleep research in normal subjects and patients with sleep disorders. gene on the mouse chromosome 1 and are currently fine mapping We have localized the first familial susceptibility gene for narcolepsy the region to ultimately identify the responsible gene. We have been and have reported the first genetic evidence in sleepwalking. Future the first to report that a single gene may dramatically affect the plans include genetics of normal sleep in twins, families, and the quantitative sleep EEG. An EEG variant specific to paradoxical sleep general population. (slow theta frequency) has been identified as the most heritable phenotype in inbred mice and subsequent mapping and functional studies identified Acads (acyl Coenzyme A dehydrogenase for short chain fatty acids) as the underlying gene. More recently, we have shown that the slow wave activity during sleep is also affected by a single gene (Rarb) involved in the vitamin A signaling pathway. We are now concentrating our research efforts on the genetic dissection of sleep need. Sleep need is homeostatically regulated (loss of sleep leads to compensatory processes, which are responsible for deep- er recovery sleep). A gene for sleep need has been mapped on the mouse chromosome 13. Gene expression profiling after sleep depri- vation to investigate the molecular correlates of prolonged wakeful- ness, identified Homer1a on chromosome 13 as the best molecular marker of sleep need. Finally, we are interested in sleep and circadi- an rhythms and their molecular basis in social species such as ants.

Mehdi Tafti received his PhD from the University of Montpellier (France) in 1991 after completing his doctoral thesis on sleep regulation in human narcolepsy. He performed a postdoctoral fellowship with Dr. Mignot and Dr. Dement and was a Research Associate at the Depart- ment of Psychiatry and Biological Sciences at Stanford University. In 1995 he moved to the Department of Psychiatry in Geneva where he established the first laboratory dedicated to the molecular genetics of sleep and sleep disorders. He joined the Center for Integrative Genomics in September 2004.

30 CIG 2007/2008 Group members Publications Funding Collaborations

Group leader research articles Tafti M, Franken P (2007) Swiss National Science B. Bettler Mehdi Tafti Rossetti AO, Heinzer R, Molecular analysis of sleep. Cold Foundation (SNSF) University of Basel, Switzerland [email protected] Espa F, Tafti M (2008) Spring Harb Symp Quant Biol • Independent Basic Y. Dauvilliers Unilateral periodic leg move- 72:573-578 Research Grant Centre Hospitalier Universitaire Postdoctoral fellows ments during wakefulness and Tafti M, Ghyselinck NB (2007) • Marie Heim Vögtlin (MHV) (CHU), Montpellier, France postdoctoral subsidy to Laure Gurcel* sleep after a parietal hemor- Functional implication of the P. Franken A. Vassalli Valérie Hinard rhage. Sleep Med 9:465-466 vitamin A signaling pathway UNIL, Lausanne, Switzerland Hyun Hor in the brain. Arch Neurol European Commission (FP6) Maret S, Dorsaz S, Gurcel L, L. Keller Anne Vassalli 64:1706-1711 Project EuMODIC Pradervand S, Petit B, Pfister C, UNIL, Lausanne, Switzerland Hagenbuchle O, O’Hara BF, comment Fondation Samuel Bouverat M. Mühlethaler PhD students Franken P, Tafti M (2007) University of Geneva, Switzerland Stéphane Dorsaz Homer1a is a core brain Tafti M (2007) Johnson & Johnson Subah Hasan* Reply to ‘Promotion of sleep U. Schibler molecular correlate of sleep UCB Pharma Stéphanie Maret* loss. Proc Natl Acad Sci U S A by targeting the orexin system University of Geneva, Switzerland Julie Vienne 104:20090-20095 in rats, dogs and humans’. Nat Med 13:525-526; Masters Student reviews author reply 526 Sébastien Del Rizzo* Andretic R, Franken P, Tafti M (2008) Technician Genetics of sleep. Annu Rev Sonia Jimenez Genet 42:361-388 Brice Petit Dauvilliers Y, Tafti M (2008) Corinne Pfister The genetic basis of sleep disorders. Curr Pharm Des Apprentice technician 14:3386-3395 Marion Graf* Tafti M (2007) Quantitative genetics of sleep Secretary in inbred mice. Dialogues Clin Annick Crevoisier Neurosci 9:273-278 [email protected] Tafti M, Dauvilliers Y, Overeem S (2007) *left the group Narcolepsy and familial advanced sleep-phase syndrome: molecu- lar genetics of sleep disorders. Curr Opin Genet Dev 17:222-227

31 Research

Bernard Thorens Molecular and physiological analysis of energy homeostasis Professor in health and disease

Glucose homeostasis and development of type 2 diabetes are criti- In a third line of investigation, we seek to identify the metaboplic cally dependent on the capacity of the insulin secreting beta-cells of pathways in liver that are associated with susceptibility or resistance the pancreas to secrete insulin according to the metabolic need of to diet-induced steatosis using comparative transcriptomic and lipi- the organism. This secretory capacity depends on both the number dodomic analysis of liver from different strains of mice. We have pre- and secretion capacity of the differentiated beta-cells. viously provided evidence that resistance to steatosis development was associated with increased expression of enzymes controlling One of our research projects aimed at identying novel genes that peroxisomal beta-oxidation and microsomal fatty acid elongation; regulate beta-cell proliferation, secretion capacity and apoptosis. lipidomic analysis has demonstrated that many lipid species were To this end we are evaluating the mode of action on beta-cells of differently produced in association with resistance to steatosis devel- the gluco-incretin hormones GLP-1 and GIP, which are known to opment. We are testing the role of these lipids in controlling insu- stimulate beta-cell precursor differentiation and proliferation of lin resistance and the proinflammatory state of the resistant mice. mature beta-cells, as well as to protect these cells against apopto- These studies are being pursued by combined transcriptomic, lipido- sis. Our ongoing work was initiated by performing transcript profil- mic and physiological analysis of mice with knockout of some of the ing of islets from mice with genetic inactivation of the GLP-1 and identified genes. These studies will investigate the functional role of GIP receptors, and which showed decreased secretion capacity and specific lipid species in controlling gene expression and the proin- increased susceptibility to apoptosis. The function of these genes is flammatory state, which is tightly associated with development of investigated by overexpression or down-expression (siRNA) studies metabolic diseases. in beta-cell lines, primary beta cells and in transgenic mice, followed by functional analysis of proliferation, apoptosis, insulin secretion, as well as whole body glucose homeostasis. Glucose homeostasis, feeding behavior and energy expenditure are under the control of the hypothalamus, where neuronal circuits inte- grate internal signals, informing on food absorption and metabolic energy storage, and send new signal to regulate energy homeostasis. In a second line of investigation we thus aim at identifying, at the cellular and molecular levels, the mechanisms by which glucose is sensed by neurons, and how these sensing neurons regulate the function of the hypothalamic neuronal circuits controlling glucose and energy homeostasis. These studies are based on the analysis of gene knockout mice, which show loss of central glucose sensing and, as a consequence, deregulated control of feeding and energy expenditure. These studies are being pursued by genetically mark- ing the glucose sensing cells to identify them and characterize the Bernard Thorens received his PhD from the University of Geneva for neuronal circuits they form to control the melanocortin pathway, a studies on the biosynthesis of immunogluobulins in pre-B lymphocytes. key hypothalamic neuronal circuit controlling glucose and energy He then did a first postdoctoral fellowship in Geneva working on homeostasis. We are also generating mice with tissue and cell-spe- hematopoietic growth factors with Pierre Vassalli. In 1986 he moved cific knockout of a glucose transporter to inactivate these glucose to the Whitehead Institute for Biomedical Research in Cambridge sensors and evaluate their role in specific anatomical sites. These (USA) for a postdoctoral fellowhisp in Harvey Lodish laboratory. In investigations involve the use of molecular biology techniques, 1991 he came back to Switzerland to take a Career Development immunohistochemistry, and integrated physiological analysis of con- award from the SNSF and to establish his laboratory at the Depart- trol or genetically modified mice. ment of Pharmacology and Toxicology. Since 2002 he is Professor on Physiology and joined the Center for Integrative Genomics in 2005.

32 CIG 2007/2008 Group members Publications Funding Collaborations

Group leader Secretary Minehira K, Young SG, Cani PD, Holst JJ, Drucker DJ, Swiss National Science R. Burcelin Bernard Thorens Danielle Canepa Del Villanueva CJ, Yetukuri L, Delzenne NM, Thorens B, Foundation (SNSF) Université de Toulouse, France [email protected] Canto-Perri Oresic M, Hellerstein MK, Burcelin R, Knauf C (2007) • Independent Basic M. Donath [email protected] Farese RV, Jr., Horton JD, GLUT2 and the incretin receptors Research Grant University of Zurich, Switzerland Preitner F, Thorens B, are involved in glucose-induced • National Centers of Postdoctoral fellows A. Geerts *left the group Tappy L (2008) incretin secretion. Mol Cell Competence in Research Isabelle Bady* Université Libre de Bruxelles, Blocking VLDL secretion causes Endocrinol 276:18-23 (NCCR) “Frontiers in Genetics“ Marie-Bernard Debril* Belgique hepatic steatosis but does not • Independent Basic Research Diana Hall Li R, Thorens B, Loeken MR affect peripheral lipid stores or grant to M.Jimenez P. Halban and C. Wollheim Maria Jimenez (2007) insulin sensitivity in mice. • Ambizione grant to K.Minehira University of Geneva, Switzerland Fabrice Marcillac* Expression of the gene encoding J Lipid Res 49:2038-2044 Matthieu Membrez* the high-Km glucose transporter SystemsX.Ch P. Herrera Kaori Minehira Poussin C, Hall D, Minehira K, 2 by the early postimplantation Project “ LipidX” University of Geneva, Switzerland research articleS Lourdes Mounien Galzin AM, Tarussio D, mouse embryo is essential for European Commission W. Krek Virginie Nepote* Ferdaoussi M, Abdelli S, Yang JY, Thorens B (2008) neural tube defects associated • Project HEPADIP (FP6) ETHZ, Zurich, Switzerland Hitomi Sanno Cornu M, Niederhauser G, Different transcriptional control with diabetic embryopathy. • Project EuroDia (FP6) C. Magnan Pascal Seyer Favre D, Widmann C, of metabolism and extracellular Diabetologia 50:682-689 • Project EuMODIC (FP6) Université Paris 7, France David Vallois Regazzi R, Thorens B, Waeber G, matrix in visceral and subcutane- • Project EDICT (FP7) Abderrahmani A (2008) ous fat of obese and rimonabant reviews P. Marchetti Société Suisse University of Pisa, Italy PhD students Exendin-4 protects {beta}-cells treated mice. PLoS ONE 3:e3385 Thorens B (2008) d’Endocrinologie et de from interleukin 1{beta}-induced Glucose sensing and the patho- M. Oresic Marion Cornu Troy S, Soty M, Ribeiro L, Diabétologie (SSE) apoptosis by interfering with the genesis of obesity and type 2 VTT, Helsinki, Finland Sonia Klinge* Laval L, Migrenne S, Young Independent Investigator c-Jun N-terminal kinases path- diabetes. Int J Obes 32 Suppl Alexandra Laverrière Fioramonti X, Pillot B, Research Grant to K. Minehira G. Rutter Nell Marty* way. Diabetes 57:1205-1215 Fauveau V, Aubert R, 6:S62-71 ICL, London, UK CardioMet Honey Modi Isken F, Pfeiffer AF, Nogueiras R, Viollet B, Foretz M, Leclerc J, Marty N, Dallaporta M, Juvenile Diabetes Research R. Scharfmann Yann Ravussin* Osterhoff MA, Ristow M, Duchampt A, Zitoun C, Thorens B (2007) Foundation International Hôpital Necker, Paris, France Audrey Sambeat Thorens B, Tschop MH, Thorens B, Magnan C, Brain glucose sensing, counter- M. Stoffel Weickert MO (2008) Mithieux G, Andreelli F (2008) regulation, and energy homeo- ETHZ, Zurich, Switzerland Masters Student Deficiency of lucose-Dependent Intestinal gluconeogenesis is a stasis. Physiology 22:241-251 Gilles Willemin* Insulinotropic Polypeptide (GIP) key factor for early metabolic Thorens B (2007) Receptor prevents ovariectomy- changes after gastric bypass Development and preclinical Bioinformatician induced obesity in mice. but not after gastric lap-band in assessment of a bioartificial Carine Poussin* Am J Physiol Endocrinol Metab mice. Cell Metab 8:201-211 pancreas. Swiss Med Wkly 137 295:E350-355 Zehetner J, Danzer C, Collins S, Suppl 155:68S-71S Technicians Klinger S, Poussin C, Debril MB, Eckhardt K, Gerber PA, Wanda Dolci Dolci W, Halban PA, Ballschmieter P, Galvanovskis J, Book Chapter Martine Emery* Thorens B (2008) Shimomura K, Ashcroft FM, Klinger S, Thorens B (2008) Joël Gyger* Increasing GLP-1-induced beta- Thorens B, Rorsman P, Molecular Biology of Gluco- Magali Joffraud cell proliferation by silencing the Krek W (2008) Incretin Function. In: Pancreatic Jean-Marie Ndoumve negative regulators of signal- pVHL is a regulator of glucose Beta Cell in Health and Disease. David Tarussio ing cAMP response element metabolism and insulin secretion Edited by Seino S, Bell GI. modulator-alpha and DUSP14. in pancreatic {beta} cells. Genes Springer 315-334 Diabetes 57:584-593 Dev 22:3135-3146

33 Research

Walter Wahli The multifaceted roles of PPARs Professor

The three Peroxisome Proliferator-Activated Receptors (PPARs) are prior to gastrulation but functions as a repressor during gastrula- nuclear receptors that act as lipid sensors to modulate gene expres- tion. All together, our data pinpoint PPARbeta as a key factor in early sion. They are implicated in major metabolic and inflammatory reg- embryo patterning. ulations with far-reaching medical consequences, and in important PPARgamma is involved in adipocyte differentiation and insulin sensi- mechanisms controlling cellular fate. PPARs exhibit a broad but iso- tivity. Synthetic ligands, the thiazolidinediones (TZD), are used as insu- type-specific tissue expression pattern, which can account for the vari- lin sensitizers in the treatment of type 2 diabetes. PPARgamma serves ety of cellular functions they regulate. This diversity of functions is also as an essential regulator of adipocyte differentiation and lipid storage, reflected by the broad range of ligands that can be accommodated and is required for maintenance and survival of mature adult adipo- within their ligand binding pocket. These ligands are naturally occur- cytes. Deregulations of its functions are thought to account for dis- ring lipids, which include diverse fatty acids, leukotrienes and prosta- eases such as obesity and diabetes. We found recently that deletion of glandins. Recently, his group has analyzed functions of the three PPAR one PPARgamma allele not only affects lipid synthesis, pentose phos- isotypes, PPARbeta (also called PPARdelta) in wound-healing, muscle phate shunt, lipolysis, and glycerol export, but also, more surprising- energy metabolism and early development of Xenopus, PPARgamma ly, networks of genes involved in IR/IGF-1 signaling, cellular integrity, in adipogenesis, and PPARalpha in liver sexual dimorphism. detoxification, and inflammation/immunity. These results unveil novel Healing of cutaneous wounds proceeds via a pattern of events includ- roles of PPARgamma in the adipose tissue and underscore the mul- ing inflammation, re-epithelialization, and tissue remodeling. We have tifaceted action of this receptor in the fine-tuned functioning of this shown that the inflammation that immediately follows injury increas- major tissue in the healthy and diseased organism. es the expression of PPARbeta and triggers the production of endog- Most metabolic studies are conducted in male animals and, conse- enous PPARbeta ligands. PPARbeta then activates a major cellular sur- quently, the molecular mechanism controlling gender-specific path- vival pathway, which protects keratinocytes from death at the site of ways has been neglected. Our recent work showed that PPARalpha injury. We have also demonstrated that transforming growth factor has broad female-dependent repressive actions on hepatic genes beta (TGFbeta1) down regulates the action of inflammation-induced involved in steroid metabolism and inflammation. Using the steroid PPARbeta, thereby participating in the coordination of re-epithelial- oxysterol hydroxylase gene Cyp7b1 as a model, we elucidated the ization. This latter event depends on directional sensing and migration molecular mechanism of this PPARalpha-dependent repression. Physi- of keratinocytes. We found that the activation of PPARbeta amplifies ologically, this repression confers protection against estrogen-induced intracellular signals required for cellular directional sensing, cell polar- intrahepatic cholestasis, suggesting a novel therapy against the most ization and pseudopodia extension. These processes are delayed and common hepatic disease during pregnancy. reduced in PPARbeta-null keratinocytes. Consistently, early wound biopsies of PPARbeta-null mice reveal uncoordinated migratory fronts Walter Wahli received his PhD from the University of Bern. He was a at the wound edge demonstrating a defect in directional sensing. postdoc at the Carnegie Institution of Washington in Baltimore, and Together, these observations reveal the molecular mechanisms by a visiting associate at the National Cancer Institute, NIH, Bethesda. which PPARbeta and its ligands contribute to wound closure. In addi- He became Professor and Director of the Institute of Animal Biology tion, PPARbeta contributes to the homeostatic control of keratinocyte of the UNIL in 1980 and was Vice-rector. He founded the CIG, which proliferation and differentiation mediated via its regulation, in dermal he directed until 2005. He has been a member of the SNSF’s research fibroblasts, of IL-1 signaling. council and presided over the Biology and Medicine Division. He We have undertaken an in depth analysis of the role of PPARs in Xen- became a member of the Swiss Science and Technology Council in opus laevis development. Down regulation of PPARbeta has dramat- 2008. He is an elected member of the EMBO and of the Institut ic effects on both gastrulation and early organogenesis. PPARbeta Jurassien des Sciences, des Lettres et des Arts. Since 2007, he is an controls gastrulation movements. At the molecular level, it regulates elected individual member of the Swiss National Academy of Medical the Nodal pathway by controlling the transcription of the 6 Nodal Sciences. He received the Otto-Naegeli Prize (2002), the European ligands (Xenopus nodal related genes 1-6; Xnr 1-6). Interestingly, Federation of Lipid Research Award (2002) and the Hartmann Müller PPARbeta behaves as a positive regulator of Xnr genes immediately Prize (2008).

34 CIG 2007/2008 Group members Publications (continued on next page)

Group leader Technicians research articles Rotman N, Terreau-Haftek Z, Indra AK, Castaneda E, Tudor C, Feige JN, Pingali H, Walter Wahli Béatrice Bordier*1 Brawand D, *Wahli W, Lücke S, Feige J, Gelman L, Antal MC, Jiang M, Lohray VB, Wahli W, [email protected] Christiane Freymond1 *Kaessmann H (2008) Desvergne B, Wahli W (2008) Messaddeq N, Meng X, Desvergne B, Engelborghs Y, Maude Husson-Delacombaz1 Loss of egg yolk genes in mam- PPAR Disruption: Cellular Mecha- Loehr CV, Gariglio P, Kato S, Gelman L (2007) Maître assistant Sonia Jimenez1 mals and the origin of lactation nisms and Physiological Conse- Wahli W, Desvergne B, Association with coregulators is Nicolas Rotman Jacqueline Kocher Braissant1 and placentation. PLoS Biol quences. CHIMIA 62:340-344. Metzger D, Chambon P (2007) the major determinant governing Catherine Morel* 6:e63. Anghel SI, Bedu E, Vivier CD, Malignant transformation peroxisome proliferator-activated of DMBA/TPA-induced papil- receptor mobility in living cells. Postdoctoral fellows Norman Moullan Jahoor A P, Bryan R, Do C, Descombes P, Desvergne B, 1 lomas and nevi in the skin of J Biol Chem 282:4417-4426. Radina Kostadinova* Corinne Tallichet-Blanc Wahli W (2007) Krier J, Watters C, Wahli W, mice selectively lacking retinoid- Alexandra Krauskopf* Adipose tissue integrity as a Wang H, Xie H, Sun X, Li G, Williams S, Rumbaugh K X-receptor alpha in epidermal Alexandra Montagner Apprentice technician prerequisite for systemic energy Tranguch S, Zhang H, Jia X, (2008) keratinocytes. J Invest Mauro Montanaro Nataska Pernet balance: a critical role for peroxi- Wang D, Das SK, Desvergne B, PPAR mediate host cell pro- Dermatol 127:1250-1260. Pipat Nawathean inflammatory responses to P. some proliferator-activated Wahli W, Dubois RN, Dey SK Zofia Terreau-Haftek* Apprentice Secretary aeruginosa autoinducer. Journal receptor gamma. J Biol Chem Mandard S, Stienstra R, (2007) Vanessa Hassler* of Bacteriology 190:4408-4415. 282:29946-29957 Escher P, Tan NS, Kim I, Stage-specific integration of PhD students Gonzalez FJ, Wahli W, maternal and embryonic *Michalik L, *Zoete V, Krey G, Berry A, Balard P, Coste A, Silvia Anghel* Secretary Olagnier D, Lagane C, Desvergne B, Muller M, PPARdelta signaling is critical Grosdidier A, Gelman L, Kersten S (2007) to pregnancy success. Ilhem Elkochairi Marlène Petit Chodanowski P, Feige JN, Authier H, Benoit-Vical F, José Iglésias [email protected] Lepert JC, Seguela JP, Glycogen synthase 2 is a J Biol Chem 282:37770-37782. Desvergne B, **Wahli W, novel target gene of peroxisome Nicolas Leuenberger **Michielin O (2007) Magnaval JF, Chambon P, *left the group proliferator-activated receptors. reviews Virginie Philippe Combined simulation and Metzger D, Desvergne B, Cell Mol Life Sci 64:1145-1157. *Michalik L, *Wahli W (2008) 1part-time mutagenesis analyses reveal Wahli W, Auwerx J, Pipy B Masters Students PPARs Mediate Lipid Signaling the involvement of key residues (2007) Stienstra R, Mandard S, Tan NS, in Inflammation and Cancer. Michaël Baruchet* for peroxisome proliferator-acti- IL-13 induces expression of CD36 Wahli W, Trautwein C, Pieric Doriot* vated receptor alpha helix in human monocytes through Richardson TA, PPAR Res 2008:134059. Henrieta Hrobova Crausaz* 12 dynamic behavior. PPARgamma activation. Lichtenauer-Kaligis E, Wahli W (2008) Francesco La Spada* J Biol Chem 282:9666-9677. Eur J Immunol 37:1642-1652. Kersten S, Muller M (2007) A gut feeling of the PXR, Emilie Person Feige JN, Gelman L, Rossi D, The Interleukin-1 receptor PPAR and NF-kappaB Rodriguez-Calvo R, Serrano L, antagonist is a direct target gene Coll T, Moullan N, Sanchez RM, Zoete V, Metivier R, Tudor C, connection. SUMMER STUDENTS Anghel SI, Grosdidier A, of PPARalpha in liver. J Intern Med 263:613-619. Merlos M, Palomer X, Laguna JC, J Hepatol 46:869-877. Sara Coleman Michalik L, Wahli W, Lathion C, Engelborghs Y, Wahli W (2008) Matteo Ricci Vazquez-Carrera M (2008) Michielin O, Wahli W, Tan NS, Icre G, Montagner A, PPAR gamma: ally and foe in Desvergne B (2007) Bordier-ten-Heggeler B, bone metabolism. Cell Metab RESEARCH SUPPORT Activation of peroxisome proliferator-activated receptor The endocrine disruptor Wahli W, Michalik L (2007) 7:188-190. monoethyl-hexyl-phthalate The nuclear hormone receptor Nathalie Constantin beta/delta inhibits lipopoly- Wahli W (2008) is a selective peroxisome peroxisome proliferator-activated saccharide-induced cytokine Nutrition, gestion de l’énergie proliferator-activated receptor receptor beta/delta potentiates production in adipocytes by et surpoids: que font donc nos gamma modulator that cell chemotactism, polarization, lowering nuclear factor-kappaB gènes? In Nouveaux Cahiers promotes adipogenesis. and migration. Mol Cell Biol activity via extracellular Volume 3. J Biol Chem 282:19152-19166. 27:7161-7175 signal-related kinase 1/2. Edited by IJSLA; 2008: 44-78. Diabetes 57:2149-2157

35 Research

Publications Funding Collaborations (continued)

*Michalik L, *Wahli W (2007) Swiss National Science P. Chambon Peroxisome proliferator-activated Foundation (SNSF) IGBMC, Illkirch, France receptors (PPARs) in skin health, Individual Basic Research grant D. Dombrowicz repair and disease. Biochim National Centers of Competence Institut Pasteur de Lille, France Biophys Acta 1771:991-998 in Research (NCCR) P. Herrera “Frontiers in Genetics“ Anghel SI, Wahli W (2007) Centre Médical Universitaire Fat poetry: a kingdom for European Commission (FP6) (CMU) – University of Geneva, PPARgamma. EuMODIC Project Switzerland Cell Res 17:486-511. Human Frontier Science C. Matter Michalik L, Wahli W (2007) Program (HFSP) University of Zurich and Univer- Guiding ligands to nuclear Postdoctoral fellowship sity Hospital Zurich, Switzerland receptors. Cell 129:649-651 to P. Nawathean D. Metzger Michalik L, Wahli W (2007) Fondation Agassiz IGBMC, Illkirch, France Roles of the peroxisome prolifer- Roche Research Foundation S. Nef ators-activated receptor (PPAR) Postdoctoral fellowship Centre Médical Universitaire alpha and beta/delta in skin to A. Montagner (CMU) – University of Geneva, wound healing. International Bioresearch and Partners, Switzerland Congress Series 1302:45-52 Monthey, Switzerland G. A. Rutter Book Chapter Imperial College, London, UK Michalik L, Wahli W. (2008) U. Schibler Tissue repair and cancer control University of Geneva, Switzerland through PPARs and their coregu- N. Soon Tan lators. In: Nuclear Receptors Nanyang Technological Co-regulators and Human University, Singapore, Singapore Disease. Edited by O’Malley B D. Trono and Kumar R; World Scientific EPFL, Lausanne, Switzerland Publishing, London, Singapore. S. Werner *both authors contributed equally ETHZ, Zurich, Switzerland to this work Bioresearch and Partners, Monthey, Switzerland **joint corresponding authors

***joint senior authors

Sex-specific sumoylation of PPARα regulates DNA methylation-dependent gene repression. The molecular mechanism of gender-specific repression of the steroid hydroxylase Cyp7b1 gene by PPARα involves sumoylation of Lysine 358 in the ligand-binding domain of PPARα. This post-translational modification is essential for the interaction of PPARα with the GA-binding protein alpha (GABPα) bound to the target promoter. Histone deacetylase (HDAC) is then recruited and, in addition, histones and adjacent Sp1-binding site are methylated. These events result in the loss of Sp1 binding to the Cyp7b1 promoter and thus, down-regulation of its activity.

36 CIG 2007/2008 Marie-Agnès Doucey Understanding signalling pathways Chargée de recherche controlling inflammatory cell functions Division of Experimental Oncology Multidisciplinary Oncology Center UNIL, Lausanne Inflammatory cells and pro-inflammatory cytokines are central in Group members Other research groups immune protection and in cancer progression. The identification of at the Génopode key signaling proteins controlling the function of inflammatory cells are of paramount significance in the design of immune protection project leader The CIG is located in the UNIL building called Génopode. This and cancer therapies. Marie-Agnès Doucey building also shelters the direction of the Swiss Institute of Bioin- In spite of the critical role of memory T cells in immune protection TechnicianS formatics (SIB) and some groups belonging to that Institute, as well and cancer progression, the biochemical mechanisms controlling the as to the Ludwig Institute for Cancer Research (LICR) and the UNIL/ diverse functional outcomes of human central and effector memory Isabelle Cohen-Salmon CHUV CePO (Multidisciplinary Oncology Center). T cell responses remain poorly understood. We implemented reverse Sylvian Bron phase protein arrays to profile T cell receptor signalling components These groups contribute greatly to the dynamism of the CIG and of PhD student the Génopode by extending further the interactions and integra- in human CD8 and CD4 memory T cells populations isolated ex vivo tion of different views, technologies and fields in research. and we identified c-Cbl as a critical regulator of the functional het- Nicolo Brembilla* erogeneity of memory CD4 T cells. *left the group Recently a distinct lineage of Tie-2/tek-expressing monocytes has been identified in peripheral blood of mouse and humans and shown to be recruited to tumor and to comprise a functionally dis- Publications tinct myeloid lineage of paracrine inducers of angiogenesis and tumor growth. These monocytes may represent a valuable marker for can- Ronet C, Voigt H, Himmelrich H, cer diagnostic and a promising target of novel anti-cancer therapies. Doucey M-A, Breton M, However, the mechanisms promoting TEM recruitment at tumor sites, Hauyon-Latorre Y, and the molecular basis of their pro-tumor and pro-angiogenic activi- Tacchini-Cottier F, Bron C, ties have not been identified yet. Our current research aims to evalu- Louis J, Launois P L (2008) ate the diagnostic value of TEM in breast cancer (in collaboration with Major-specific B cells are neces- Professor J.-F. Delaloye, University Hospital (CHUV), Lausanne) and to sary for Th2 cell development gain insight into the signalling pathways and the molecular mecha- and susceptibility to infection nisms controlling their functions by interfacing computational and with L. Major LV39. J. Immunol experimental approaches (in collaboration with Dr. Ioannis Xenarios, 80:4825-35 Vital-IT). Finally, to characterization the soluble factors that mobilize Brembilla N C, Weber J, angiogenic monocytes to the tumor, we are currently constructing a Rimoldi D, Schütz F, biosensor based on functionalized silicon nanowires for the label-free Pantaleo G, Rüegg C, detection of pro-inflammatory and angiogenic factors in breast tumor Quadroni M, Harshman K, extracts (in collaboration with Dr. Hourlier, CNRS, Lille, France). Doucey M-A (2008) Cbl expression levels regulate the functional responses of human memory CD4 T cells. Blood 112:652-60

37 Research

Victor Jongeneel Cancer genomics CIG Associate Professor ad Personam

Swiss Institute of Bioinformatics (SIB) Ludwig Institute for Cancer Research (LICR) The research interests of the group focus on two major themes: Group members Publications Retelska D, Beaudoing E, • the evolution and variability of the genes encoding cancer- Notredame C, Jongeneel CV, testis antigens Hofmann O, Caballero OL, Bucher P (2007) Group leader Stevenson BJ, Chen YT, Cohen T, Vertebrate conserved non • the development of in silico techniques for the efficient analysis Victor Jongeneel Chua R, Maher CA, Panji S, coding DNA regions have a high of novel high-throughput genomics data. [email protected] Schaefer U, Kruger A, persistence length and a short CT genes are normally expressed only in immuno-privileged cells of Lehvaslaiho M, Carninci P, persistence time. BMC Genomics the germ line, but re-expressed in a variable proportion of cancers. Associate investigator Hayashizaki Y, Jongeneel CV, 8:398 Most of the human genes with a strict CT expression pattern are Brian Stevenson Simpson AJ, Old LJ, Hide W Moretti S, Armougom F, localized on the X chromosome, and are members of families that (2008) Wallace IM, Higgins DG, have undergone recent expansion in the primate lineage. One focus assistant investigator Genome-wide analysis of cancer/ Jongeneel CV, Notredame C of our research is to trace the evolutionary history of CT-X genes. Christian Iseli testis gene expression. Proc Natl (2007) To this end, we are establishing a comprehensive catalogue of CT-X Acad Sci U S A 105:20422 The M-Coffee web server: genes in the human genome, which is a challenging task because PhD Student Rougemont J, Amzallag A, a meta-method for computing many of them occur in regions with segmental duplications that Armand Valesia Iseli C, Farinelli L, Xenarios I, multiple sequence alignments by have not been assembled correctly or contain gaps. This work has Naef F (2008) combining alternative alignment led us to identify new CT-X families and to produce more detailed editorial assistant & Probabilistic base calling methods. Nucleic Acids Res genomic maps of known families. We are also looking for CT homo- database curator of Solexa sequencing data. 35:W645-8 logues in the ever increasing collection of available genomes, with Monique Zahn BMC Bioinformatics 9:431 Pagni M, Ioannidis V, the goal of tracing the emergence and evolution of each family, and Sauvain MO, Dorr AP, Cerutti L, Zahn-Zabal M, therefore inferring possible function. Finally, we are studying copy Stevenson B, Quazzola A, Jongeneel CV, Hau J, number variations (CNV) of CT-X genes, both at the genetic (inter- Naef F, Wiznerowicz M, Martin O, Kuznetsov D, individual differences) and the somatic (cancer-specific) levels. Schütz F, Jongeneel V, Falquet L (2007) On the methodological side, we have developed tools for the effi- Duboule D, Spitz F, Trono D MyHits: improvements to an cient utilization of short reads generated by “next-generation” (2008) interactive resource for analyzing sequencing machines. The “Rolexa” algorithm makes it possible Genotypic features of lentivirus protein sequences. Nucleic Acids to interpret and map a significantly larger proportion of individu- transgenic mice. J Virol 82:7111-9 Res 35:W433-7 al reads from Solexa/Illumina sequencers than the manufacturer’s Alves PM, Lévy N, Stevenson BJ, Iseli C, Ambrosini G, Bucher proprietary software. The “fetchGWI” software implements a very Bouzourene H, Theiler G, P, Jongeneel CV (2007) efficient method for matching large collections of short sequences Bricard G, Viatte S, Ayyoub M, Indexing strategies for rapid to genome-size databases, facilitating SNP inference. We have also Vuilleumier H, Givel JC, searches of short words in evaluated methodologies for extracting reliable CNV information Rimoldi D, Speiser DE, genome sequences. PLoS ONE from genome-wide hybridization data in very large cohorts. Jongeneel CV, Romero PJ, 2:e579 Lévy F (2008) Stevenson BJ, Iseli C, Panji S, Identification of tumor-asso- Zahn-Zabal M, Hide W, Old ciated antigens by large-scale LJ, Simpson AJ, Jongeneel analysis of genes expressed in CV (2007) human colorectal cancer. Rapid evolution of cancer/testis Cancer Immun 8:11 genes on the X chromosome. BMC Genomics 8:129

38 CIG 2007/2008 Olivier Michielin Molecular modeling, in silico drug design and protein engineering Assistant Professor for the development of cancer therapies Swiss Institute of Bioinformatics (SIB) Ludwig Institute for Cancer Research (LICR) The Molecular Modeling group studies mechanisms of molecu- Group members Publications lar recognition, in particular protein-protein or protein-small ligand interactions. The group develops and employs molecular modeling Grosdidier A, techniques such as homology modeling, molecular dynamics, pro- Group leader Zoete V. Michielin O (2007) tein-ligand docking, structure-based fragment-based drug design Olivier Michielin EADock: docking of small and free energy simulations. Most efforts are concentrated on the [email protected] molecules into protein active development of new small molecule inhibitors of important targets sites with a multiobjective for cancer therapy, as well as the design of optimized peptides vac- Research supervisor evolutionary optimization. cines or T Cell Receptor (TCR) sequences for cancer immunotherapy. Vincent Zoete Proteins 67:1010-25 In silico structure-based ligand design is becoming a very attractive Zoete V, Michielin O (2007) alternative to high throughput in vitro methods. We have developed Postdoctoral fellows Comparison between compu- the EADock docking program, which uses a very accurate and uni- Loay Awad tational alanine scanning and versal scoring function to provide a good description of molecular Michel Cuendet per-residue binding free energy interactions from small fragments up to complete ligands. An effi- Aurélien Grosdidier decomposition for protein- cient conformational search engine has been designed based on an Melita Irving protein association using evolutionary algorithm. We are currently using a fragment-based Justyna Iwaszkiewicz MM-GBSA: application to the approach to design specific inhibitors of important cancer targets Ute Röhrig TCR-p-MHC complex. Proteins for which several micro and nano-molar compounds have been Thierry Schuepbach 67:1026-47 obtained lately. Cuendet MA, Michielin O PhD Student Specific cellular immune responses are based on the recognition by (2008) Mathias Ferber cytotoxic T lymphocytes of immunogenic peptides presented in the Protein-protein interaction investigated by steered molecu- context of the class I Major Histocompatibility Complex (MHC). TCR Technician sequence modifications designed to improve recognition of a giv- lar dynamics: the TCR-pMHC Sylvian Bron en p-MHC complex represent a very attractive approach since these complex. Biophys J 95:3575-90 modified sequences can be incorporated in the patient’s lympho- cytes using viral vectors and used in an adoptive transfer setting. We have developed several free energy calculation methods not only to dissect TCR-p-MHC interactions, but also to interpret the effect of a mutation and guide peptide and/or TCR modifications. Sever- al mutations proposed by the in silico approach have recently been shown to improve TCR affinity as well as tumor cell killing by trans- fected lymphocytes in vitro.

39 facilities ore

40 CIG 2007/2008 C 41 Core Facilities

Keith Harshman Lausanne DNA Array Facility (DAFL) Maître d’Enseignement et de Recherche

The goal of the Lausanne DNA Array Facility (DAFL) is to provide Educational Activities the user community with access to the state-of-the-art technologies used to measure quantitative and qualitative variations in nucleic The DAFL is also active as an educational resource for the communi- acids. The principal technology platforms supported by the DAFL to ty. Its principal activities have been in organizing a yearly week-long achieve this goal are: microarray use and application course under the auspices of the Schweizerische Kommission fuer Molekularbiologie (SKMB) and the • The Illumina Genome Analyzer II and the 454 Genome IIIème Cycle Romand en Sciences Biologiques. Additionally, the DAFL Sequencer FLX ultra high throughput DNA sequencing assists in the planning and organization of the Lausanne Genom- instruments ics Days Symposium, a 2 day event in which invited scientist present • Affymetrix GeneChip oligonucleotide arrays for the analysis on recent developments in genomic research in molecular biology, of mRNA and DNA medicine, ecology and evolution. • Illumina BeadChip oligonucleotide arrays for the analysis of mRNA • Agilent oligonucleotide arrays for the analysis of small non-coding RNA • the Applied Biosystems 7900HT Sequence Detection System for as quantitative real-time PCR analyses • sample handling robots for the production of custom spotted DNA and protein arrays The DAFL provides users with training and supervision in all aspects of the molecular biology and instrument manipulations associated its technology platforms. In many cases, the DAFL will perform all of the steps of the experiment, beginning with nucleic acids provided by the user. A key aspect of the DAFL service platform is the bioinfor- matics support and consultation service it provides at the stages of experimental design, data collection and storage, image analysis and, when appropriate, higher level data analysis. The facility allows users to carry out their experiments in its laboratories by providing equip- ment and bench space. Furthermore, the DAFL maintains computer workstations and software with which users can analyze their data. Keith Hashman received his PhD in biochemistry from the California Institute of Technology in 1990 working in the laboratory of Carl Parker on the isolation and characterization of eukaryotic transcription factors. Following post doctoral fellowships with Walter Schaffner at the University of Zurich and Dennis Ballinger at the Sloan-Kettering Cancer Center, in 1993 he joined Myriad Genetics Inc. where he worked first as a Senior Scientist and later as the Director of Central Nervous System Disease Research. In 1997 he moved to the Depart- ment of Immunology & Oncology of the Spanish National Biotechnol- ogy Center in Madrid as the Head of the Functional Genomics Unit. He has been the Coordinator of the Lausanne DNA Array Facility since November of 2002.

42 CIG 2007/2008 Group members Publications

director Brembilla NC, Weber J, Wirapati P, Sotiriou C, Kunkel S, Keith Harshman Rimoldi D, Pradervand S, Farmer P, Pradervand S, Acknowledgements [email protected] Schutz F, Pantaleo G, Haibe-Kains B, Desmedt C, in publications Ruegg C, Quadroni M, Ignatiadis M, Sengstag T, BioinformaticIANs Harshman K, Doucey MA Schutz F, Goldstein DR, As a core facility, the DAFL receives ackowledgement but not Sylvain Pradervand (2008) Piccart M, Delorenzi M (2008) authorship on publications containing results obtained from regular Darlene Goldstein* c-Cbl expression levels Meta-analysis of gene expres- services. Authorships reflect extensive collaborations beyond regu- Emmanuel Beaudoing regulate the functional sion profiles in breast cancer: lar services. responses of human central and toward a unified understanding effector memory CD4 T cells. of breast cancer subtyping and Within the years 2007 and 2008, the DAFL was ackowledged in at miRNA, custom spotted Blood 112:652-660 prognosis signatures. Breast more than 30 publications in the following journals: arrays, qPCR and UHT Cancer Res 10:R65 SEQUENCING Gaillard M, Pernet N, Vogne C, • Aging Cell • Hum Mol Genet Johann Weber Hagenbuchle O, Maret S, Dorsaz S, Gurcel L, Hannes Richter van der Meer JR (2008) Pradervand S, Petit B, Pfister C, • BMC Bioinformatics • J Bacteriol Manuel Bueno* Host and invader impact of Hagenbuchle O, O’Hara BF, • Breast Cancer Res • J Biol Chem Floriane Consales transfer of the clc genomic island Franken P, Tafti M (2007) into Pseudomonas aeruginosa Homer1a is a core brain • Cancer Res • Lancet Oncol Affymetrix PAO1. Proc Natl Acad Sci U S A molecular correlate of sleep • Cell • Mol Cell Biol Otto Hagenbüchle 105:7058-7063 loss. Proc Natl Acad Sci U S A • Cell Stem Cell • Mol Cell Neurosci 104:20090-20095 Alexandra Paillusson Pradervand S, Paillusson A, • Curr Biol • Nature Sophie Wicker Thomas J, Weber J, Wirapati P, • Dev Cell • Nature Medicine Hagenbuchle O, Harshman K secretary (2008) • Plant Cell • Plant Cell Fabienne Sauvain Affymetrix Whole-Transcript • Genome Biol • PLoS Genet Human Gene 1.0 ST array is [email protected] • Genome Res • Proc Natl Acad Sci U S A highly concordant with standard *left the group 3’ expression arrays. • Hepatology • PLoS ONE Biotechniques 44:759-762 Runne H, Regulier E, Kuhn A, Zala D, Gokce O, Perrin V, Sick B, Aebischer P, Deglon N, Luthi-Carter R (2008) Dysregulation of gene expres- sion in primary neuron models of Huntington’s disease shows that polyglutamine-related effects on the striatal transcriptome may not be dependent on brain cir- cuitry. J Neurosci 28:9723-9731

43 Core Facilities

Manfredo Quadroni Protein Analysis Facility (PAF) Maître d’Enseignement et de Recherche

Analysis of cells at the protein level directly targets the main players Collaborative studies on functionally related in cellular processes and gives access to events that cannot be stud- sets of proteins ied by genomics and transcriptomics. Proteomics techniques have evolved considerably in the last decade and are now sufficiently We have continued collaboration with the group of M. Peter (ETHZ, mature to analyze complex systems and cellular pathways in detail. Zurich, Switzerland) focused on the study of protein complexes In addition to determine protein expression levels, it is nowadays formed by the E3 Ubiquitin ligases Cullin-3 and Cullin-4A. We were possible to study protein complexes and post-translational modifi- able to show specific association of Cul-3 with a family of Kelch cations. The PAF supports the UNIL research community in all tasks domain-containing proteins (KLH-9, -13, -21 and others), while Cul- in this field, utilizing both protein and peptide-level separation tech- 4A recruited WD40-domain containing proteins instead. All these niques coupled with mass spectrometry as an analytical tool. molecules are believed to be recruiting subunits which determine the set of substrates ubiquitinated by each E3 ligase complex. The Cul-3- KLH9-KHL13 complex was later shown to play a key role in mitosis. Improved offer of services Another collaboration with the group of C. Ruegg (Multidisciplinary In 2007-2008 the PAF has expanded its offer to include support for Oncology Center (CePO), Lausanne) has led us to determine a set of analysis of phosphorylation in complex samples (phosphoproteom- cell surface proteins which localize in lipid rafts and are candidate ics) as well as SILAC (Stable Isotope Labeling with Amino Acids in markers of metastatic melanoma. In the context of a third collab- Culture) experiments for quantitative proteomics. We have in addi- orative effort with the group of M. Monod (Dermatology, Universi- tion improved the sensitivity of our analyses as well as the quality of ty Hospital (CHUV), Lausanne, Lausanne) we were able to complete data analysis and experiment reporting provided to users. Our ser- the first comprehensive identification of the proteins secreted by the vice of shotgun protein identification aimed at discovering protein- two skin infecting fungi Trychophyton rubrum and Trychophyton protein interactions has grown in popularity – the number of analy- violaceum. This fraction is highly enriched in proteases, which play a sed samples has doubled over previous years. role in the invasion of the skin layers, but surprisingly was found to contain numerous other hydrolases such as lipases and glycosidases Independent technology development projects whose role in pathogenesis remains largely unknown. We have pursued our development of methods for metabolic label- ing of cells to specifically identify in complex mixtures such as whole cell extracts the proteins that were synthesized at high rates during a given time. We have applied variants of these labeling protocols to study changes in protein turnover in cells infected by Herpes Simplex virus. We found several molecules display changes, the functional importance of which is under investigation. As a second application Manfredo Quadroni got his PhD in Biochemistry at the ETHZ, Zurich, we have devised a strategy to explore the pool of proteins secreted Switzerland in 1996 working with E.Carafoli and P. James on protein by human cell lines (the “secretome”) under regular culture condi- analysis techniques applied to calcium signaling molecules. He complet- tions. The presence of a vast excess of bovine serum proteins makes ed his first postdoctoral training at the University of British Columbia, the analysis of these samples particularly challenging. The experience Canada, in the group of Prof. J. Schrader, with focus on the pro- we accumulated with stable isotope labeling with amino acids has teomics analysis of cell signaling complexes in immunology. His second resulted, among other things, in the development of a novel method postdoctoral training brought him back at ETHZ, Zurich, Switzerland of relative protein quantification. This new technique (termed ISIS) is (1998–2000) to work on development of methods for proteome anal- based on labeling with isobaric amino acid analogs which give rise to ysis. He was then Maître assistant at the Institute of Biochemistry of distinct reporter ion fragments in tandem MS spectra. the UNIL between 2000 and 2003. He joined the CIG in March 2003 as Maître d’Enseignement et de Recherche (MER) to coordinate the PAF facility.

44 CIG 2007/2008 Group members Publications Funding and Collaborations

director Brembilla NC, Cohen-Salmon I, Giddey K, Favre B, Quadroni M, Funding Manfredo Quadroni Weber J, Ruegg C, Quadroni M, Monod M (2007) Swiss National Science Acknowledgements [email protected] Harshman K, Doucey MA Closely related dermatophyte Foundation (SNSF) in publications (2009) species produce different pat- Independent Basic Coordinator Profiling of T-cell receptor terns of secreted proteins. Research Grant As a core facility, the PAF receives ackowledgement but not author- at the GENOPODE signaling complex assembly in FEMS Microbiol Lett 267:95-101 ship on publications containing results obtained from regular services. Patrice Waridel human CD4 T-lymphocytes Giddey K, Monod M, Collaborations Authorships reflect extensive collaborations beyond regular services. using RP protein arrays. Barblan J, Potts A, Waridel P, J.–J. Diaz and A. Greco Within the years 2007 and 2008, the PAF was ackowledged for BioinformaticianS Proteomics 9:299-309 Zaugg C, Quadroni M (2007) INSERM, Lyon, France example in publications in the following journals: Gnanasekaran Thoppae Baruthio F, Quadroni M, Comprehensive analysis of pro- Ruegg C, Mariotti A (2008) teins secreted by Trichophyton M. Peter Céline Hernandez • Brain Res Bull • Proteomics Proteomic analysis of membrane rubrum and Trichophyton viola- ETHZ, Zurich, Switzerland Technicians rafts of melanoma cells identifies ceum under in vitro conditions. C. Ruegg • Circ Res • Vox Sang Jachen Barblan protein patterns characteristic J Proteome Res 6:3081-3092 University Hospital (CHUV) and • Mol Biol Cell Alexandra Potts of the tumor progression stage. Grill B, Bienvenut WV, UNIL, Lausanne, Switzerland Proteomics 8:4733-4747 Brown HM, Ackley BD, M. Monod PhD student Brembilla NC, Weber J, Quadroni M, Jin Y (2007) University Hospital (CHUV) and Mara Colzani Rimoldi D, Pradervand S, C. elegans RPM-1 regulates axon UNIL, Lausanne, Switzerland Schutz F, Pantaleo G, Ruegg C, termination and synaptogenesis Quadroni M, Harshman K, through the Rab GEF GLO-4 and Doucey MA (2008) the Rab GTPase GLO-1. Neuron c-Cbl expression levels regu- 55:587-601 late the functional responses Sumara I, Quadroni M, Frei C, of human central and effector Olma MH, Sumara G, Ricci R, memory CD4 T cells. Blood Peter M (2007) 112:652-660 A Cul3-based E3 ligase removes Colzani M, Schutz F, Potts A, Aurora B from mitotic chro- Waridel P, Quadroni M (2008) mosomes, regulating mitotic Relative protein quantification by progression and completion isobaric SILAC with immonium of cytokinesis in human cells. ion splitting (ISIS). Dev Cell 12:887-900 Mol Cell Proteomics 7:927-937 Tinel A, Janssens S, Lippens S, Da Cruz S, Parone PA, Cuenin S, Logette E, Jaccard B, Gonzalo P, Bienvenut WV, Quadroni M, Tschopp J (2007) Tondera D, Jourdain A, Autoproteolysis of PIDD marks Quadroni M, Martinou JC the bifurcation between pro- (2008) death caspase-2 and pro-survival SLP-2 interacts with prohibitins NF-kappaB pathway. in the mitochondrial inner mem- Embo J 26:197-208 brane and contributes to their stability. Biochim Biophys Acta 1783:904-911

45 Core Facilities

The Bioinformatics Core Facility (BCF) The Cellular Imaging Facility (CIF)

The Bioinformatics Core Facility (BCF) is a research and service The Cellular Imaging Facility (CIF) was created in 2003 to assist CORE FACILITIES ASSOCIATED group, member of the Swiss Institute of Bioformatics (SIB), located researchers with imaging needs ranging from wide-field fluores- WITH THE CIG within the Génopode. The BCF offers consulting, data analysis sup- cence and transmission optical microscopy, confocal microscopy, port, training and research collaborations. Our core competences time-lapse and ion imaging, to digital image processing and analysis. In addition to the DNA array facility (DAFL) and the protein and activities reside in the interface between biomedical sciences, Since the end of 2005, the CIF has extended its activities on the analysis facility (PAF), a number of other core facilities are asso- statistics and computation, particularly in the application of high- Dorigny campus. throughput omics technologies in biochemical, translational and ciated with the CIG, either because they are located in the The CIF is organized around three complementary activities: Génopode and/or because they are directed by CIG members. clinical research, such as the study of gene-gene and gene-pheno- type associations and biomarker development. Main activities: Such facilities contribute greatly to the dissemination of novel • Service activities: Investigators of the Faculty of Biology and techniques and know-how, to the highly interactive atmo- • Data Analysis Support and Biostatistics Consulting: We provide Medicine and associated institutions are offered access to a sphere of the CIG, and thus to the quality and creativity of the panel of state-of-the-art imaging equipment and techniques. research at the CIG and beyond. basic bioinformatic and data analytic support at all stages of high-throughput studies, from design to data acquisition, • Training: The CIF shares and diffuses the practical and theoretical analysis, and interpretation. The consulting service is run on know-how on these approaches through teaching and training. a mandate from - and partially funded by - the SIB and A series of lectures on cellular imaging are being given yearly. the Swiss Confederation. Practical training on the instruments are provided in the form • Training: We train researchers in the application of basic of short “hands-on” courses, even individual, throughout the methods of data analysis and interpretation through year, and workshops on various aspects of imaging organized course and workshop offerings. for pre- and post-graduate students. • Research and Collaborations: We can provide collaborative • Research: Technological Development . In parallel to service data analysis and method implementation for projects activities, a consortium of investigators affiliated with the requiring advanced or innovative approaches to academic CIF will develop and implement most advanced optical and and industrial partners. imaging technologies. This unit will have an open and dynamic interface with the service, so that emerging technological The emergence of “omics” science presented challenges for inte- developments will be implemented and rendered accessible grating multiple modes of assays (DNA, RNA, proteins) and het- to more users of the CIF. erogeneous, independent datasets (multi-center cohorts in clinical studies). We develop solutions for data curation and management, The CIF existence is the result of a joint financial and structural effort application of rigorous statistical methods and implementation of of the Faculty for Biology and Medicine (FBM) of the UNIL and the effective and efficient computational methods. University Hospital (CHUV), Lausanne. The hosting institutes have also brought a major contribution by offering room, infrastructure, DIRECTOR logistics, administrative, and technical support. Mauro Delorenzi DIRECTOR [email protected], [email protected] Jean-Yves Chatton BIOSTATISTICS CONSULTING [email protected] Frédéric Schütz TECHNICAL MANAGER AT THE CIG [email protected] Arnaud Paradis WEBSITE [email protected] http://bcf.isb-sib.ch/ WEBSITE Statistical support: [email protected] General enquires: [email protected] http://cifweb.unil.ch/

46 CIG 2007/2008 Center for Investigation The Mouse Metabolic Vital-IT and Research in Sleep (CIRS) Evaluation Facility (MEF)

Sleep disorders are very prevalent, and represent an “emerging The Mouse Metabolic Evaluation Facility (MEF) was created in 2006 Vital-IT is an innovative life science informatics initiative providing worldwide epidemic”. However, despite an impressive progress dur- as the result of a joint financial and structural effort of the Center for computational resources, consultancy and training to connect fun- ing the last 3 decades, biological and molecular bases of most sleep Integrative Genomics in the Faculty of Biology and Medicine (FBM) of damental and applied research. It is a collaboration between the disorders remain unknown. Consequently, almost all available treat- the UNIL, the University Hospital (CHUV), Lausanne and the NCCR, Swiss Institute of Bioinformatics (SIB), the UNIL and University of ments for sleep disorders are symptomatic and not evidence-based. Frontiers in Genetics. The MEF is located in the Génopode. Geneva, the Ludwig Institute for Cancer Research (LICR), the EPFL, Given their variety and impact on different biological systems (res- Lausanne, and industrial partners. These partners form an alliance The mission of the MEF is to provide the Lausanne and Swiss Research piration, metabolism, motor control, cognition), a multidisciplinary of unrivalled expertise in the processing and analysis of biological Community with a wide repertoire of state-of-the-art, standardized approach is needed, not only for understanding the pathophysiol- information. Using their complementary competencies, they provide investigative techniques to analyze the metabolic status of mice mod- ogy but also for diagnosis and treatment of sleep disorders. fundamental science and leading edge technology for the construc- els of complex human disorders. tion of a world-class high-perfomance computing platform, and the Thus, in collaboration with clinicians specialist in sleep disorders, we Given the high level of complexity of most techniques, the MEF pro- expertise to allow it to be exploited effectively for solution of both have established the Center for Investigation and Research in Sleep vides services to the researchers. The MEF also provides teaching for scientific and commercial problems. (CIRS). This joint venture between the CIG and the University Hos- those who want to introduce specific techniques into their own lab- pital (CHUV), Lausanne, is providing a state-of-the-art infrastruc- Vital-IT provides infrastructure and computational expertise to sup- oratories. In order to broaden the scope of phenotyping tests, the ture to conduct high level basic and clinical research and to offer to port research conducted primarily by its partners, and develops MEF aims also at developing new investigation techniques in part- the community the highest standard for diagnosis and treatment of hardware and software solutions to allow research results to be nership with laboratories at the UNIL, the CHUV and the EPFL, Lau- sleep disorders. turned into products. Additionally, the group serves as an interface sanne, Switzerland. between academic research and the commercial world. The main DIRECTORS The MEF is an integral part of the CHUV-FBM CardioMet Research activities undertaken by Vital-IT are: Mehdi Tafti (CIG) Center that gathers three coordinated investigative units, namely the • Providing an HPC environment to support the research work of its [email protected] MEF, the Rodent Cardiovascular Phenotyping Center (coordinated by partners, in areas ranging from sequence analysis through molecu- Prof. T. Pedrazzini, at the FBM) and the Clinical Investigation Center lar modelling, genomics, proteomics and image analysis Raphael Heinzer (CHUV) (coordinated by Prof. F. Pralong at CHUV). Cardiomet aims at foster- • Developing specialist software engineering techniques for paral- [email protected] ing joint projects in clinical and basic research, in the Cardiovascular and Metabolic fields. lelization, optimization and validation of complex algorithms. WEBSITE • Development activities to turn concepts derived from research into www.unil.ch/cig/page42710_fr.html Director robust software solutions. Bernard Thorens • Consulting and educational activities geared towards the compu- [email protected] tational needs of companies in the life sciences. • Acting as an agent for new collaborations with industry and in Coordinator future, including potential spin-off of new companies in the field Frédéric Preitner of life-science informatics. [email protected] DIRECTOR WEBSITE Ioannis Xenarios www.cardiomet.ch/cmet_home/cardiomet-chercheurs/cardiomet- [email protected] chercheurs-plateforme_metabolique.htm WEBSITE www.vital-it.ch

47 48 CIG 2007/2008 education 49 Education

Courses and lectures given by CIG members

EDUCATION AT THE CIG Courses at the UNIL Bachelor level Master level PhD level A central mission of the CIG is education. The members of the CIG, whether research group leaders, research assistants or members of Béatrice DESVERGNE Liliane MICHALIK Béatrice DESVERGNE Christian FANKHAUSER core facilites, give courses at the Bachelor, Master and PhD levels Génétique avancée Biologie cellulaire animale Régulation transcriptionnelle Paul FRANKEN at the UNIL and at other organizations. The CIG is also active in Biologie et société Embryologie du métabolisme Circadian clocks the organization of undergraduate studies, for example with the Biologie animale et génétique I Alexandre REYMOND Christian FANKHAUSER Winship HERR involvment of C. Fankhauser in the organization of the UNIL Mas- Biologie animales et génétique II BCM: du génome au phénome Structure des génomes Reasoning and logic in ter GBE (Genomics and Experimental Biology), see www.unil.ch/ Béatrice DESVERGNE Statistiques pour biologistes des végétaux genetics and molecular and enseignement/page28113_en.html. co-instructor: Andrzej STASIAK Effets de l’environnement cellular biology CIG research groups comprise researchers at every stage of their Nicolas ROTMAN Mechanism of DNA sur le développement Alexandre REYMOND training, including not only post-doctoral fellows and PhD stu- (maître-assistant) recombination Christian FANKHAUSER Mapping transcription start sites dents, but also students working toward their master degree in Génétique avancée Mehdi TAFTI Johann Weber Bernard THORENS Biology. Moreover, during the summer, the CIG hosts pre-gradu- Biologie animale et génétique II BCM – du phénome au génome Cartographie, séquençage Introduction endocrinologie 2.1 ate students through a summer research program run by the EPFL Béatrice DESVERGNE et structure des génomes Métabolisme glucidique 2.4 School of Life Sciences in collaboration with the CIG (see http://ssv. Liliane MICHALIK epfl.ch/page64103.html). Postdoctoral fellows and graduate stu- Paul FRANKEN Walter WAHLI Keith HARSHMAN dents, who spend several years doing research at the CIG, benefit co-instructor: from a mentoring program (see p. 52). Mehdi TAFTI Nicolas ROTMAN Johann WEBER Beyond formal courses, research is learnt through interactions (maître-assistant) Génomique protéomique and collaborations with colleagues. To favor formal and informal Biologie cellulaire animale et génétique quantitative exchanges, the CIG organizes an annual retreat as well as numer- Nouria HERNANDEZ Winship HERR ous internal and external seminars and symposia. Walter WAHLI Virologie Transcription et maturation Last but not least, a number of educational activities are directed de l’ARN Henrik KAESSMANN towards the public at large. Alexandre REYMOND Nouria HERNANDEZ Evolutionary and co-instructor: comparative genomics Erwann VIEU (maître-assistant) Liliane MICHALIK Travaux pratiques structurés Embryologie Winship HERR Manfredo QUADRONI From genotype to phenotype Alexandra POTTS and phenotype to genotype Jachen BARBLAN Proteomics: introduction Henrik KAESSMANN Introduction to molecular Bernard THORENS evolution PPP métabolisme Molecular evolution Walter WAHLI Chapitres choisis de développement Récepteurs nucléaires et régulation génétique

50 CIG 2007/2008 Undergraduate students

Courses at other organizations Summer students Master students

Paul FRANKEN Alexandre REYMOND Frederic LAURENT David BARRAS Andrea MARAN Genetics of sleep (PhD level) The human genome project Group Herr Group Michalik Group Fankhauser Regulation of sleep (PhD level) (Bachelor level) Jovan MIRCETIC Michaël BARUCHET Group Franken European Marie Curie Teaching University of Geneva Group Hernandez Group Michalik Sophie NICOD courses Functional genomics (PhD level), Cylia ROCHAT Group Wahli Group Kaessmann EPFL, Lausanne, Switzerland Otto HAGENBÜCHLE Group Martin Claire BERTELLI Emilie PERSON Methods for transcriptome Mehdi TAFTI Ana TUFEGJZIC Group Hernandez Group Wahli analysis (Master level) Neurobiologie des états Group Herr Vincent CROSET Marianne RENAUD EPFL, Lausanne, Switzerland de vigilance (Master level) Vanja VUKOJEVIC Group Benton Group Hernandez Otto HAGENBÜCHLE University of Geneva Group Fankhauser Nicolas DARMONT Aurélie RIGHETTI Keith HARSHMAN Bernard THORENS Group Michalik Group Michalik Johann WEBER Integration by the brain of Fang WANG Group Fankhauser RNA expression profiling using peripheral signals to control Cynthia DAYER Fabian SCHWEIZER DNA microarrays energy homeostasis Zhou ZHOU Group Herr Group Fankhauser Group Franken (Master/ PhD level) (PhD level) Group Martin Sebastien DEL RIZZO 3e Cycle Romand en Sciences NCCR Frontiers in Genetics Group Tafti Deborah WIDMER Group Benton Biologiques Walter WAHLI Pieric DORIOT Nouria HERNANDEZ Thiazolidinediones et autres Group Wahli Gilles WILLEMIN Biologie moléculaire II approches médicamenteuse Diego GONZALES Group Thorens (Bachelor level) (Bachelor level) Group Herr EPFL, Lausanne, Switzerland University of Geneva Henrietta HROBOVY Exercice de biologie Walter WAHLI CRAUSAZ (Bachelor level) co-instructor: Group Hernandez EPFL, Lausanne, Switzerland Nicolas ROTMAN Group Wahli Liliane MICHALIK (maître-assistant) Francesco LA SPADA PPARs: skin repair and cancer Récepteurs nucléaires Group Wahli (PhD level) (PhD level) Frédéric LAURENT NCCR Frontiers in Genetics NCCR Frontiers in Genetics Group Michalik Manfredo QUADRONI Lionel MAQUELIN FT-ICR mass spectrometry Group Kaessmann (Master level) University of Geneva

51 Education

The mentoring program PhD theses Prizes awarded to CIG students and postdoctoral fellows

The CIG has organized a support program, in which each PhD stu- Silvia ANGHEL Jérôme FEIGE Doing A Phd At The Cig dent selects a member of the CIG Faculty as an academic mentor. Group Wahli Group Desvergne This mentor provides support and advice during the PhD studies, PPARgamma and adipose Prix d’Excellence du jeune chercheur Education and support to graduate students is a central concern and can act as a reference later. In principle, the academic mentor tissue functions (2007) 2007 of the Faculty of Biology of the CIG. All PhD students at the Center are part of the doctoral works on a different topic than the one pursued by the PhD student, Subah HASAN and Medicine (FBM), UNIL school of the UNIL Faculty of Biology and Medicine (FBM), which as this helps to provide different points of view and broadens hori- determines the program and regulations of PhD studies. Group Tafti Yaël GROSJEAN zons and connections. Comment garder le cerveau Group Benton In addition, the CIG set up a mentoring program to support and The academic mentoring program is one arm of a two-tier mentor- éveillé? Pharmacogénomique Poster prize at the D.Day 2008, advise graduate students. Through the program, each student is ing scheme, in which students receive guidance from both a research et effets du vieillissement sur UNIL, awarded by the Société coupled to a mentor, in general a faculty member working in a dif- mentor and an academic mentor. The research mentor is the thesis la régulation veille-sommeil Vaudoise des Sciences Naturelles ferent field than the one pursued by the graduate student, who is advisor. The academic mentor is an interested, and impartial, faculty chez la souris cosanguine (2008) Chitose KAMI available for scientific or non-scientific discussions and advice. member chosen to provide diversity in the student’s education. Charlotte HENRICHSEN Group Fankhauser Opportunities to learn about different research topics and tech- Group Reymond Best poster 2008 at the 25th nologies are numerous, for example during the annual CIG retreat, The Role of the mentoring program and of Structure et fonction du génome: Annual Missouri Plant Biology which is attended not only by all CIG groups but also by all other Academic Mentors de l’homme à la souris (2008) Symposium research groups in the Génopode, or the annual CIG symposium, To provide graduate students with the unique experience of having Stéphanie MARET Stéphanie MARET which is organized every year by different CIG faculty members on close contact with a senior member of the scientific community Group Tafti Groups Franken and Tafti a topic of interest to CIG scientists. The CIG seminar series brings La dissection génétique Sponsors Award (2008) for every week external leading scientists from all over the world, who • To provide graduate students with a faculty member whose primary concern is their academic development des oscillations lentes du Outstanding Basic Sleep give their presentation and then spend time discussing with inter- cerveau durant le sommeil Research, awarded by the ested students and post-doctoral fellows. • To provide graduate students with a letter of reference chez la souris (2007) Société Suisse de Recherche The CIG is proud to support the activities of the “CIG Association • To act as a conduit Ana MARQUES sur le Sommeil, de Médecine of Scientists” CAOS, which groups students, post-doctoral fellows, Group Kaessmann du Sommeil et de Chronobiologie and technicians. In particular, the “Careers for Biologists Seminars” see also: www.unil.ch/cig/page62072.html The role of gene duplication Stéphanie MARET feature speakers with a biology training and a career outside of the in the origin and evolution of Groups Franken and Tafti university environment. They come to share with the audience the new biological functions (2008) Prix Guenin 2008 steps that led them to their present position and their professional Nicolas VINCKENBOSCH Ana MARQUES experience. Group Kaessmann Group Kaessmann The number of PhD students has considerably increased with the Understanding mutational and Prize of the Faculty of Biology development of the Center over the past few years and is now selective processes that govern and Medicine (FBM), UNIL, more than 40, with students from many different nationalities and gene duplication in mammals for her PhD thesis (2008) backgrounds. On the other hand, we have seen the first gradu- (2008) Marianne RENAUD ations, as the students who started their PhD research when the Group Hernandez CIG was being set up completed their thesis projects. Prize of the Faculty of Biology see also www.unil.ch/cig/page62067.html and Medicine (FBM), UNIL, for her Master’s thesis (2008)

52 CIG 2007/2008 PhD students The CIG Association of Scientists (CAOS) Careers for biologists seminars

Imtiyaz AHMAD Matthew HALL Yann RAVUSSIN CAOS, or CIG Association of Scientists, is an association founded by Jérôme BILLOTTE Group Desvergne Group Desvergne Group Thorens the PhD students and postodctoral fellows of the CIG, which any CIG Strategos and Amethis Monica ALBARCA Subah HASAN Jaime Humberto REINA member may join. The association has three main aims: Lausanne, Switzerland Group Herr Group Tafti Group Hernandez Emilie BRICAUD Silvia ANGHEL Charlotte HENRICHSEN Marianne RENAUD science Roche Diagnostics Rotkreuz, Switzerland Group Wahli Group Reymond Group Hernandez Among the scientific activities of the CAOS are: Rati BELL Patricia HORNITSCHEK Raphaël RYTZ Andreas FÜRHOLZ • the organization of regular CIG junior scientists meetings, Group Benton Group Fankhauser Group Benton Nestlé Research Center during which students and postdoctoral fellows present Lausanne, Switzerland David BRAWAND José IGLÉSIAS Audrey SAMBEAT and discuss their work with their peers. Group Kaessmann Group Wahli Group Thorens Rolf MARTI • the organization of a yearly conference (the Lausanne Life Swiss Cancer League Jean-Marc BRUNNER Philippe JULIEN Magali SOUMILLON Science Festival) with leading scientists from Switzerland Bern, Switzerland Group Desvergne Group Kaessmann Group Kaessmann and abroad Luca ROSSI Francesca CAPOTOSTI Sonia KLINGER Raphaël TERRIER Philip Morris International R&D Group Herr Group Thorens Group Michalik future Neuchâtel, Switzerland Evelyne CHAIGNAT Kyriakos KOKKORIS Sajit THOTTATHIL OOMMENT With the aim of helping the CIG junior scientists to plan their Magdalena SKIPPER Group Reymond Group Martin Group Desvergne career in academic fields or in industry after they obtain their PhD, Nature Reviews Genetics Mara COLZANI Francesco LA SPADA Julie VIENNE the association organizes: London, UK Group Quadroni – PAF Group Franken Group Tafti • Career for Biologists Seminars: these monthly seminars give the Marion CORNU Alexandra LAVERRIÈRE Nicolas VINCKENBOSCH opportunity to students to discover different career possibilities Group Thorens Group Thorens Group Kaessmann for PhDs Dimitry DEBRIEUX Nicolas LEUENBERGER Marta WAWRZYNIAK • workshops to help students to develop particular skills, Group Fankhauser Group Wahli Group Michalik for example, write their CV Matthieu DE CARBONNEL Stéphanie MARET Robert WITWICKI • Some occasional events such as the participation to the EPFL Group Fankhauser Group Tafti Group Reymond Job Forum Davide DEMURTAS Ana MARQUES Group Stasiak Group Kaessmann social Stéphane DORSAZ Nell MARTY Informal meetings are an important tool for junior scientists to build Group Tafti Group Thorens bonds, which will remain important thourough their career. CAOS Ilhem ELKOCHAIRI Honey MODI thus organizes social, cultural and throughout events which are open Group Wahli Group Thorens to all CIG personnel including students, postdocs, professors, and Vincent FIECHTER Virginie PHILIPPE technical and administrative staff. Group Fankhauser Group Wahli see also: http://www3.unil.ch/wpmu/caos/scientific/ He FU Lukasz POTRZEBOWSKI Group Desvergne Group Kaessmann Sophie GUERNIER Cédric HOWALD Group Herr Group Reymond

53 Education

CIG seminars

Geneviève ALMOUZNI Laurent DURET Michael HALL Andreas MAYER Seminars And Symposia Curie Institute, Paris, France Université Claude Bernard Lyon 1, University of Basel, Switzerland UNIL, Lausanne, Switzerland Chromatin assembly factors, Villeurbanne, France TOR signaling and control of cell Organelle dynamics as The integrative nature of the CIG, with its different research fields, histone H3 variants and The mystery of intron splicing growth in yeast and mammals determined by molecular model organisms and technologies, as well as its location among the cell cycle Russell G. FOSTER Christine HARTMANN coordination of membrane other first rate research institutions, make it an ideal place to hear fusion and membrane and learn about different fields of research. Wendy BICKMORE Imperial College London, UK IMP, Vienna, Austria MRC Human Genetics Unit, Light, clocks and sleep: Skeletal lineage decision fragmentation Interactions with external scientists is of central importance. The Edinburgh, UK the signalling pathways – a matter of beta-catenin Andrew MILLAR CIG organizes a series of weekly seminars (the CIG seminar series) Nuclear reorganisation, of photosensitive retinal Elisa IZAURRALDE University of Edinburgh, UK and co-organizes together with other departments of the FBM the chromatin decondensation, ganglion cells Max Planck-Institute for Unwinding the biological clock “BIG” (Biology and Integrative Genomics) seminars. In addition, and the regulation of gene Tom GINGERAS Developmental Biology, with systems biology many ad hoc seminars are organized independently by CIG faculty expression during differentiation Affymetrix Inc, Santa Clara, USA Tübingen, Germany Ove NILSSON members. In 2008, the CIG organized a special series of seminars and development Transcriptional landscape of How do miRNAs silence gene Swedish University of to select a new Swiss National Science Foundation (SNSF) “profes- Cathrin BRISKEN the human genome: interlaced expression? Agricultural Sciences, seur boursier” candidate for the Department. ISREC/EPFL, NCCR Molecular model for genome organization Daniela KAUFER Uppsala, Sweden The CIG symposium, organized yearly by CIG faculty members (see Oncology, Lausanne, Switzerland Pierre GONCZY University of Califormia, The evolutionary conserved page 58), offers the possibility to explore a particular field during Genetic dissection of ISREC/ EPFL, Lausanne, Switzerland Berkeley, USA CO/FT regulon controls plant the course of one and half day, during which invited leading scien- signalingpathways in breast Mechanisms of centrosome Stress as a model for brain growth and development in tists in that particular field present their work. CIG members are development and breast cancer duplication in C. elegans plasticity response to seasonal variation also involved in the co-organization of numerous other symposia, in photoperiod Gerhard CHRISTOFORI and beyond Brigitte KIEFFER conferences, and advanced courses (see p. 59). University of Basel, Switzerland Rolf GRUETTER University Louis Pasteur, Allan PACK Distinct mechanisms of tumor EPFL, Lausanne, Switzerland Illkirch, France University of Pennsylvania, invasion and metastasis Perspectives on functional Opioid receptors, pain and Philadelphia, USA Manolis DERMITZAKIS genomics with functional, addiction: genetic approaches Functional genomic approaches to the study of sleep The Wellcome Trust Sanger molecular and metabolic Steve KOWALCZYKOWSKI Institute, Cambridge, UK imaging University of California, Tatiana PETROVA Causes and patterns of Ingrid GRUMMT Davis, USA CHUV/UNIL, Lausanne, Switzerland regulatory variation in the German Cancer Research Center, Visualization and analysis of FOXC2 and PROX1 in lymphatic human genome Heidelberg, Germany protein-DNA complexes at vascular development and Barry DICKSON Non-coding RNA and chromatin the single-molecule Level cancer University of Vienna, Austria remodeling: Intergenic Wilhelm KREK Chris PONTING Wired for sex: genetic and transcripts regulate the ETHZ, Zurich, Switzerland University of Oxford, UK neutral control of Drosophila epigenetic state of rRNA genes The von Hippel Lindau tumor Travels through exotic genomes: mating behaviour Ernst HAFEN suppressor: a central controller from platypus to us? Gian Paolo DOTTO ETHZ, Zurich, Switzerland of energy metabolism and Richard REDON UNIL, Lausanne, Switzerland Genetics of growth control tissue growth The Wellcome Trust Sanger Notch signaling: a key node in in Drosophila Cris KUHLEMEIER Institute, Cambridge, UK the control system network of Thanos HALAZONETIS University of Bern, Copy number variation in keratinocyte stem cell potential University of Geneva, Switzerland Switzerland humans and chimpanzees: new and carcinogenesis DNA damage checkpoints Mathematical modeling insights in evolution and disease and cancer of phyllotaxis

54 CIG 2007/2008 Ad hoc seminars

Marc ROBINSON-RECHAVI Magdalena ZERNICKA-GOETZ “Professeur Boursier” Remi TERRANOVA David BENTLEY Laura CATO UNIL, Lausanne, Switzerland University of Cambridge, UK Candidates Friedrich Miescher Institute (FMI), Illumina Inc, Cambridge, UK University of Cambridge, UK Constraints and opportunities Pluripotency, plasticity and cell Basel, Switzerland The Illumina Genome Analyzer: A tale of the tail: investigating Jeroen DOBBLELAERE after vertebrate whole genome fate in the early mouse embryo Polycomb and nuclear technology and applications the interaction between linker Wellcome Trust Sanger Institute, duplication organization in development for ultra high throughput histones and HMGB1 Cambridge, UK and cell differentiation sequencing Carmen SANDI Genome-wide analysis in Mark CHAISSON EPFL, Lausanne, Switzerland Roxane BLATTES University of California, BIG Seminars organized Drosophila for genes involved Neurobiological mechanisms in centrosome maturation Université Paul Sabatier, San Diego, USA involved in the interactions by CIG members other “Ad Hoc Toulouse, France De novo assembly of short reads Jacques FELLAY between stress and memory seminars” Molecular basis of position using EULER 3.0 Peter FRASER Duke University, Durham, USA formation The Babraham Institute, Emilie AIT YAHYA GRAISON effect variegation in Drosophila HIV host genomics Frédéric CHALMEL Dirk SCHUEBELER Cambridge, UK Université de Paris Diderot, melanogaster Université de Rennes, France Thomas FLATT Friedrich Miescher Institute (FMI), Transcription and nuclear Paris 7, France André BRAENDLI The Annotation, Mapping, Brown University Providence, USA Basel, Switzerland organization of the genome Classification of chromosome 21 ETHZ, Zurich, Switzerland Expression and Network (AMEN) Endocrine regulation of aging Epigenome reprogramming Susan GOTTESMANN gene expression variations Molecular insights into suite of tools and its applications and reproduction in Drosophila during lineage commitment National Institutes of Health in Down Syndrome segmentation of the vertebrate to the conserved transcriptome and terminal differentiation (NIH), Bethesda, USA Pierre FONTANILLAS Grigoris AMOUTZIAS nephron in mammal spermatogenesis Harvard University Cambridge, USA of stem cells Biological circuits with Small RNA UNIL, Lausanne, Switzerland Donatella CANELLA Fred CHANG Gene expression and genome Michele SOLIMENA Switches A protein interaction atlas for Michigan State University, Columbia University, organization Technical University, Anthony HYMAN the nuclear receptors: properties East Lansing, USA New York, USA Dresden, Germany MPI for Molecular Cell Biology David GATFIELD and quality of a hub-based Characterization of the Shaping cells with microtubules University of Geneva, Switzerland dimerisation network How do pancreatic beta cells and Genetics, Dresden, Germany Arabidopsis CBF1 transcription Wah CHIU MicroRNAs as inputs and count their secretory granules Systems approaches to cell division Hubert AMREIN factor: functional role of Baylor College of Medicine, outputs of the circadian clock Markus STOFFEL Thomas JENTSCH Duke University, Durham, USA two evolutionarily conserved Houston, USA ETHZ, Zurich, Switzerland Leibniz-Institut für Molekulare Johannes JAEGER Taste and pheromone perception signature sequences Cryo-electron microscopy Forkhead transcription factors Pharmakologie, Berlin, Germany University of Cambridge, UK in Drosophila Carles CANTO of viruses Shift happens: The and the control of metabolism Function and dysfunction of Ulrike BAUER University Louis Pasteur, Damien COLAS developmental and evolutionary Françoise STUTZ vesicular chloride transport: University of Technology, Illkirch, France Fondation Rita Levi-Montalcini, dynamics of the gap gene University of Geneva, Switzerland insights from mouse Berlin, Germany Regulation of muscle metabolism Rome, Italy network Anti-sense RNA stabilization and Combinatorial biosynthesis by neuregulins and Evidence for peripheral orexin transcriptional gene silencing in Samuel MARGUERAT for the generation of A47934 AMP-activated protein kinase signaling in the dorsal root yeast S. cerevisiae Wellcome Trust Sanger derivatives Leonardo CAPPONI ganglia; implications in pain Institute, Cambridge, UK Elisabetta ULLU Felipe BENDEZU University of Geneva, Switzerland sensing Dynamic repertoire of the fission Yale University, New Haven, USA Case Western Reserve University, Study of microRNA 155 in a Raja DUVVURU yeast transcriptome surveyed at RNAi machineries in trypanosomes Cleveland, USA new mouse dendritic cell line University of Fribourg, Switzerland single-nucleotide resolution Bacterial actin and cell shape Bas VAN STEENSEL Cristina CASALS CASAS Genetic and nutritional Andrew SHARP determination in Escherichia coli Netherlands Cancer Institute University of Barcelona, Spain regulation of arbuscular University of Geneva, Switzerland Amsterdam, The Netherlands Zsigmond BENKO Plasticity of AP-1 regulated mycorrhizal symbiosis: lessons Discovery of recurrent genomic Genome – nuclear lamina University of Debrecen, Hungary genes of the immune system from Petunia disorders from the duplication interactions HIV and heat shock proteins: architecture of the human anti-vpr activities of heat shock genome proteins 55 Education

Ad hoc seminars (continued)

Vivien EXNER David GONZALEZ David HERNANDEZ Philippe JULIEN Robb KRUMLAUF Nicole MALGRAS ETHZ, Zurich, Switzerland Trinity College, HUG, Geneva, Switzerland EMBL, Heidelberg, Germany Stowers Institute for Medical ETHZ, Zurich, Switzerland Functions of CAF-1 and its Dublin, Ireland Whole bacterial genome eggNOG: a new database to Research, Kansas City, USA Functional characterization subunits in Arabidopsis Novel human genes derived sequencing: de novo assembly study orthologous groups Hox genes and regulation of the Killer Protein 6 produced Anne FISCHER from non-coding DNA of very short reads Evangelia KALLIVRETAKI of head development by the basidiomycete Ustilago MPI for Evolutionary Gilbert GREUB Wassim HODROJ University of Bern, Switzerland Arun KUMAR maydis Anthropology, Leipzig, Germany UNIL/CHUV Université Claude Bernard, Functional significance Institute of Genomics Ernest MARTINEZ Genetic variation in great apes Lausanne, Switzerland Lyon, France of aromatase in zebrafish and Integrative Biology University of California, Johan FLYGARE Genome Sequencer 20 and Caractérisation fonctionnelle during development New Dehli, India Riverside, USA Lund University, Sweden Genome Sequencer FLEX for de l’angiotensine IV dans le Ioannis KARAKASILIOTIS Stress, metabolism and cell Multiprotein complexes Towards gene therapy of de novo genome sequencing: développement des maladies Imperial College London, UK death: connecting the dots in regulation of chromatin, Diamond-Blackfan Anemia local experience cardiovasculaires et du diabète Interaction of Hepatitis C virus Karine LAPOUGE transcription & MYC de type 2 oncoprotein functions David FURLOW Yaël GROSJEAN with the host hypoxia response UNIL, Lausanne, Switzerland University of California, University of Illinois, Chicago, USA James HSIEH Jim KENT Global regulation of biocontrol Cristian MICHELETTI Davis, USA Genderblind: a glial transporter Washington University, University of California, metabolites in Pseudomonas International School for Amphibian metamorphosis: a that regulates glutamatergic St-Louis, USA Santa Cruz, USA fluorescens CHA0 Advanced Studies (SISSA), model system for understanding synapse strength to control The Taspase1 proteolytic Comparative genomics – Frédéric LEMOINE Trieste, Italy nuclear receptor control of Drosophila mate choice signaling pathway links MLL algorithms and observations Université Paris Sud, France Dynamics-based alignment: to cell cycle and beyond a novel tool for comparing development Olivier HACHET Sander KERSTEN Integration, querying and large-scale movements in Peter GALLANT ISREC/ EPFL, Lausanne, Switzerland Wolfang HUBER Wageningen University, analysis of prokaryotic proteins with the same or University of Zurich, Switzerland Mid1p/anillin and the Septation EBI/EMBL, Cambridge, UK The Netherlands comparative genomics data different folds Control of size by Drosophila Initiation Network orchestrate Automated image analysis for Regulation of metabolism by Manyuan LONG Myc: mechanisms o contractile ring assembly high-throughput cell-based PPARa and angiopoietin-like University of Chicago, USA Sohan MODAK transcriptional regulation for cytokinesis microscopy assays with R and protein 4 New gene evolution in Institute of Genomics and bioconductor Integrative Biology, Delhi, India Benjamin GANTENBEIN Christoph HANDSCHIN Piyush KHANDELIA Drosophila: phenotype and Darwins dream: construction AO Research Institute (ARI), University of Zurich, Switzerland Nahid IGLESIAS Indian Institute of Science, mechanism of multiparametric phylogenetic Davos, Switzerland Metabolic and anti-atrophic University of Geneva, Switzerland Bangalore, India Marina LUONGO tree in 3D space Molecular evolutionary rates functions of PGC-1alpha The ubiquitin pathway regulates Diverged functions for conserved University of Salerno, Italy in protein-coding genes of Marc HEIJDE multiple steps of fission yeast splicing factors Changes in membrane Gaëlle MONGELARD Mex67-mediated mRNA export University of Bern, Switzerland scorpions Ecole Normale Supérieure, Kyriakos KOKKORIS physical state regulate Zinc transport in plants: Robert GENTLEMAN Paris, France David JAMES University of Uppsala, Sweden the phosphorylation of characterization of new Zn Fred Hutchinson Cancer Light responses and Garvan Institute of Medical RNA binding properties of ERK 1/2 in PC-3 cells transporters in Solanum Research Center, Seattle, USA functional characterization Research, Sidney, Australia poly(A)-specific riibonuclease David MAGNANI of Cryptochromes in Insulin action and the path lycopersicum and Assessing the role played by Anders KROGH University of Bern, Switzerland Phaeodactylum tricornutum of most resistance Arabidopsis thaliana multi-protein complexes in University of Copenhagen, Novel components of copper Mauro MONTANARO determining phenotype and Ostreococcus tauri Nicole JAMES FARESSE Denmark homeostasis in bacteria Universidad Nacional de La Plata, David GFELLER Christophe HELIGON University of Geneva, Switzerland Computational methods for Buenos Aires, Argentina University of Toronto, Canada ETHZ, Zurich, Switzerland Role of the Ccr4-Not complex finding transcription factor Regulation of fatty acid Specificity and cross-reaction in Wnt/Frizzled signaling during in transcription initiation in the binding sites in promoter desaturases in diabetes PDZ interaction networks pronephric kidney development yeast Saccharomyces cerevisae sequences mellitus rat models

56 CIG 2007/2008 Anamaria NECSULEA Laure QUIGNODON Pierre-Yves RISOLD Koichiro SHIOKAWA Juliane TROEGER Akadiri YESSOUFOU Université de Lyon, France Ecole Normale Supérieure, Université de Besançon, France Teikyo University, Tokyo, Japan University of Zurich, Switzerland Université d’Abomey-Calavi, The relationship between DNA Lyon, France Anatomie des systèmes Cloning of Xenopus Phospholipid stimulation and Cotonou, Bénin replication and human genome Mouse genetic to understand producteurs de l’hormone de S-adenosylmethionine downstream target identification Rôle de PPARalpha et des organization how Thyroid Hormone mélano-concentration (MCH) decarboxylase (SAMDC) and of the PAS domain kinase acides gras oméga-3 dans Edward OAKELEY Receptor alpha 1 controls et hypocrétines/oréxines (Hcrt) discovery of maternal program PASKIN la modulation du diabète Friedrich Miescher Institute (FMI), neurodevelopment dans l’hypothalamus du rat of apoptosis executed at David VALLOIS gestationnel et de la macrosomie Basel, Switzerland Oliver RAU Ida RUBERTI midblastula transition (MBT), INSERM, Paris, France Keji ZHAO Gene expression on Affymetrix Johann Wolfgang Goethe CNR Institute of Molecular with a few slides about our new Genetics factors and type 1 National Institutes of Health tiling and exon arrays University, Frankfurt Biology and Pathology Department of Judo Therapy diabetes development in the (NIH), Bethesda, USA Teresa ODORISIO am Main, Germany Rome, Italy Mehmet SOMEL NOD mouse Characterization of human Istituto Dermopatico Orphan receptors adopting Regulatory networks for the MPI for Evolutionary Laurie VUILLET epigenomes dell’Immacolata IRCCS, phytochemicals – PPAR shade avoidance response Anthropology, Leipzig, Germany Université de Montpellier, France Philip ZIMMERMANN Rome, Italy a case study Hitomi SANNO Our juvenile brains: brain Bacteriophytochromes and ETHZ, Zurich, Switzerland Placenta Growth Factor in David RECTOR University of Heidelberg, maturation at the gene control of Light Harvesting Meta-profiling microarray data skin angiogenesis and repair Washington State University, Germany expression level in humans Complexes synthesis in provides another perspective and chimpanzees François PARCY Pullman, USA Rho GTPases play a role in Rhodopseudomonas palustris on gene expression CNRS/INRA/CEA/ Grenoble High speed optical imaging proper formation of layer IV Li-Ping (Bolin) SONG Zhenghui WANG University, France of the brain and V in sometosensory cortex Institute of Health Sciences, University of Québec, Canada Structure and evolution Florent REVEL Alexandra SAPETSCHNIG Shanghai, Rep. of China The role of oxidative stress in of the LEAFY floral regulator Université Louis Pasteur, Philipps-University Marburg, Differentiation-inducing therapy: heat shock-induced apoptosis hypoxia and leukemic cell Heidi PETERSON Illkirch, France Germany in Chinese hamster ovary cells differentiation Estonian Biocenter, Neuroendocrine Orchestration of Mechanisms of SUMO-mediated Martin WELLS Tartu, Estonia Seasonal Physiology – Focus on transcriptional repression Caroline TAUXE Nonlinear Dynamics / Geneva Using gene expression for Reproduction Christoph SCHMID UNIL/CHUV, Lausanne, Switzerland Bioinformatics (Genebio) SA, pathway (re)construction Michael RHODES Swiss Institute of Bioinformatics Regulation of P-selectin Geneva, Switzerland Sergio POLAKOF Applied Biosystems, (SIB) and ISREC/EPFL, Lausanne, glycoprotein ligand 1 Seminar and workshop in University of Vigo, Spain Foster City, USA Switzerland (PSGL-1) interactions with quantitative proteomics selectins: role of the decamers Glucose intolerance in fish: SOLiDTM System A revolution ChIP-seq – new prospects Jonathan WIDOM and of the cytoplasmic domain from glucose sensing to in next generation sequencing for transcriptional regulation Northwestern University, nutrient interaction technology Kristina SCHOONJANS Juilee THAKAR Evanston, USA Peter QUAIL Guénola RICARD University Louis Pasteur, University of Maryland, The genomic code for University of California, Berkeley, Radboud University Nijmegen Illkirch, France University Park, USA nucleosome positioning Modeling systems-level and Plant Gene Expression Medical Centre, The Netherlands Role of LRH-1 in health and Yanfang YE regulation of host immune Center, Albany, USA Evolution and genome structure disease Osaka City University, Japan responses Phytochrome photosensory of anaerobic Ciliates Molecular functions of signaling networks geranylgeranyl diphosphate synthase in fission yeast

57 Education

CIG Symposium 2008: Metabolism and Cancer

Organizers Matej ORESIC selected talks Cig Symposium N. Hernandez, B. Thorens, VTT Technical Research W. Wahli Centre of Finland, Espoo, Finland Michelangelo FOTI Encouraged by the success of its inaugural symposium in 2005, University of Geneva, Switzerland Johan AUWERX Metabolomics in diabetes the CIG decided to establish a yearly symposium on a few broad topics Unsaturated fatty acids promotes University Louis Pasteur, research that would rotate every year. Accordingly, the CIG symposium is hepatocytes proliferation Illkirch, France now organized every year by the CIG director and CIG faculty mem- Philipp SCHERER and carcinogenesis through bers whose research is connected to the topic explored that year. Transcriptional cofactors as UT Southwestern Medical Center downregulation of the tumor master regulators of metabolism at Dallas, USA supressor PTEN The CIG symposium encourages interactions between junior and Sadaf FAROOQI The role of the adipocyte in senior scientists. Thus, junior scientists can submit abstracts and metabolism and cancer Barbara HAENZI University of Cambridge, UK FMI, Basel, Switzerland present their work during a poster session or through oral presen- Regulation of human appetite Bruce SPIEGELMAN tations selected from the abstracts. Role of Memo in premature and body weight: insights from Dana-Farber Cancer Institute aging and breast cancer see also: www.unil.ch/cigsymposium genetics Harvard Medical School, Sander KERSTEN Philippe FROGUEL Boston, USA Transcriptional control of energy Wageningen University, Institut Pasteur de Lille, France The Netherlands Genome wide associations homeostasis in health and disease Exploring the role and regulation studies bring breakthrough in of Angptl4 in mouse and human obesity, diabetes and associated Antonio VIDAL-PUIG metabolic disorders University of Cambridge, UK Stéphanie MARET Adipose tissue expandability, GUENIN PRIZE 2008 Grahame HARDIE UNIL, Lausanne, Switzerland University of Dundee, UK lipotoxicity and the metabolic syndrome Homer1a is a core brain AMP-activated protein kinase: molecular correlate of sleep loss a drug target in metabolic Eileen WHITE disorders and in cancer? Rutgers University, Rudolf KAAKS Piscataway, USA German Cancer Research Tumor suppression by autophagy Center, Heidelberg, Germany through management of Nutritional energy balance and metabolic stress cancer; epidemiological evidence for the implication of metabolic and hormonal risk factors Daniel P. KELLY Washington University School of Medicine, St. Louis, USA Cardiac nuclear receptor signaling in health and disease

58 CIG 2007/2008 USGEB 2008 Lausanne Genomics Days Biology Meets Engineering

Organizers Monitoring Global Magnus NORDBORG Ecological and Symposia Co-Organized By The Cig W. Herr, H. Kaessmann, Changes in Gene University of Southern California, Evolutionary A. Reymond, B. Thorens, Expression (2007) Los Angeles, USA Genomics (2008) Symposia were co-organized with the following partners: C. Brisken, H. Lashuel, Edward RUBIN T. Lasser, S. Sidjanski, Organizers Organizers • Department of Ecology and Evolution (DEE), UNIL K. Harshman, S. Pradervand, DOE Joint Genome Institute, C. Fankhauser, P. Reymond, O. Staub, M. Swartz, Walnut Creek, USA • Department of Medical Genetics (DGM), UNIL D. Trono, G. van der Goot O. Hagenbüchle, V. Jongeneel, M. Robinson-Rechavi, • Department of Plant Molecular Biology (DBMV), UNIL M. Delorenzi, J. Beckmann Gregory VELICER F. Naef, L. Keller Naama BARKAI Indiana University, • EPFL, Lausanne, Switzerland Weizmann Institute Rudolf AEBERSOLD Douglas L. CRAWFORD ETHZ, Zurich, Switzerland Bloomington, USA University of Miami, USA • University of Geneva, Switzerland of Science, Rehovot, Israel Uri ALON Michael HERMAN • Swiss Institute for Bioinformatics (SIB) Mitra HARTMANN Northwestern University, Weizmann Institute, Kansas State University, • USGEB (Union of the Swiss Societies for Experimental Biology) Evanston, USA Rehovot, Israel Biological Networks Manhattan, USA Laurent KELLER Jean-Laurent CASANOVA and Complex Traits Molly PRZEWORSKI UNIL, Lausanne, Switzerland Université de Paris, France (2008) University of Chicago, USA Stanislas LEIBLER Philippe FROGUEL Organizers David QUELLER The Rockefeller University, Institut Pasteur de Lille, K. Harshman, O. Hagenbüchle, Rice University, Houston, USA New York, USA France, J. Beckmann, F. Naef, Amira SEHGAL Uwe SAUER Robert KINGSTON M. Robinson-Rechavi University of Pennsylvania, ETHZ, Zurich, Switzerland Massachusett General Marc BIGGIN Philadelphia, USA Hospital, Boston, USA Pamela SILVER Lawrence Berkeley Laboratory, Dani ZAMIR Harvard University Inder VERMA Berkeley, USA Hebrew University, Tel Aviv, Israel Boston, USA Salk Institute, San Diego, USA Edwin CUPPEN Melody A. SWARTZ Hubrecht Institute, EPFL, Lausanne, Switzerland Utrecht, The Netherlands Ecological Jonathan FLINT and Evolutionary Wellcome Trust Sanger Genomics (2007) Institute, Cambridge, UK Andrew C. OATES Organizers MPI Dresden, Germany C. Fankhauser, L. Keller, P. Reymond Richard REDON Wellcome Trust Sanger Andrew CLARK Institute, Cambridge, UK Cornell University, Ithaca, USA Jussi TAIPALE Charalambos KYRIACOU University of Helsinki, Finland Leicester University, UK Sarah MATTHEWS Harvard University, Cambridge, USA

59 Education

SKMB Gene Regulation Workshop Implementing 1st Aneuploidy FENS 2008 Satellite Symposium: the “Collaborative Workshop Sleep Function: Approaches towards Cross” in Lausanne the Roles of Sleep in Neuronal Functions

Organizers Organizers Organizers Organizers David RECTOR N. Hernandez, F. Karch, P. Franken, W. Herr, D. Trono A. Reymond, J. Wuarin, P. Franken, C. Kopp, University of Washington, USA W. Reith, M. Strubin Gary CHURCHILL S. E. Antonarakis H.-P. Landolt, A. Lüthi Dieter RIEMANN The Jackson Laboratory, Emmanouil T. DERMITZAKIS IIsabelle ARNULF University of Freiburg i.Br., 2007 2008 Bar Harbor, USA Wellcome Trust Sanger Institute, INSERM, Paris, France Germany Bruno AMATI Denise BARLOW Richard MOTT Cambridge, UK Claudio BASSETTI Mehdi TAFTI University of Milan, Italy University of Vienna, Austria Oxford University, UK Evan EICHLER University Hospital Zurich, UNIL, Lausanne, Switzerland Anne EPHRUSSI Claude DESPLAN David THREADGILL University of Washington, Switzerland Daniel ULRICH EMBL, Heidelberg, Germany New York University, USA University of North Carolina, Seattle, USA J. BORN Trinity College Dublin, Ireland Witold FILIPOWICZ Mitzi KURODA Chapel Hill, USA Uta FRANCKE University of Lübeck, Germany Raphaëlle WINSKY-SOMMERER FMI, Basel, Switzerland Harvard University, Boston, USA Rob WILLIAMS Stanford University, Christian CAJOCHEN University of Zurich, Switzerland Palo Alto, USA Shiv GREWAL Carol PRIVES University of Tennessee, University of Basel, Switzerland National Cancer Institute, Columbia University, Memphis, USA Katheleen GARDINER Derk-Jan DIJK Bethesda, USA New York, USA University of Denver, USA University of Surrey, UK Steven HAHN Mark PTASHNE Craig GARNER Marcos FRANK Hutchinson Cancer Research Sloan-Kettering Institute, Stanford University, University of Pennsylvania, Center, Seattle, USA New York, USA Palo Alto, USA Philadelphia, USA James MANLEY Wolf REIK Matt HURLES Paul FRANKEN Columbia University, The Babraham Institute, Wellcome Trust Sanger UNIL, Lausanne, Switzerland New York, USA Institute, Cambridge, UK Cambridge, UK Reto HUBER Tim RICHMOND Rick YOUNG James R. LUPSKI University Children’s Hospital ETHZ, Zurich, Switzerland Whitehead Institute, Baylor College of Medicine, Zurich, Switzerland Houston, USA Cambridge, USA J. KRUEGER Chengbiao WU Washington State University, Stanford University, Pullman, USA Palo Alto, USA Hanspeter LANDOLT Roger H. REEVES University of Zurich, Switzerland Johns Hopkins University, Pierre-Hervé LUPPI Baltimore, USA University of Lyon, France Steve W. SCHERER Anita LÜTHI The Hospital for Sick Children, University of Basel, Switzerland Toronto, Canada Michel MÜHLETHALER Orsetta ZUFFARDI University of Geneva, Switzerland Università degli Studi di Pavia, Italy Eugene YU Roswell Park Cancer Institute, Buffalo, USA

60 CIG 2007/2008 Ultra High Throughput Sequencing Genes Genomes and Evolution

1st meeting: 2ND MEETING: Organizers Dan TAWFIK Computational UHT APPLICATIONS L. Keller, H. Kaessmann, Weizmann Institute The CIG is grateful to the Analysis of UHT AND CHALLENGES A. Reymond, X. Perret, of Science, Rehovot, Israel following organizations who Sequencing DatA O. Hagenbüchle Organizers Alan WEINER made these events possible Organizers K. Harshman, S. Pradervand, I. Christoph ADAMI University of Washington, USA K. Harshman, P. Bucher, Xenarios, J. Rougemont, CalTech, Pasadena, USA Peter YOUNG Affymetrix L. Falquet, C. Iseli C. Iseli, P. Descombes Daniel BARBASH University of York, UK Schweizerische Gesellschaft für Physiologie Loïc BAERLOCHER Jean-Louis BLOUIN Cornell University Ithaca, USA Evgeny ZDOBNOV Agilent Technologies ème Fasteris SA, Geneva, Switzerland University of Geneva, Switzerland Ralph GREENSPAN University of Geneva, Switzerland Fondation du 450 Applied Biosystems Neurosciences Institute, anniversaire de l’UNIL Laurent FARINELLI Stewart COLE Axon Lab Fasteris SA, Geneva, Switzerland EPFL, Lausanne, Switzerland San Diego, USA Fonds du Dr. E. Rub Katrin HENZE Biolabo Scientific David HERNANDEZ Laurent FARINELLI Swiss Society of Sleep Instruments Hôpitaux Universitaires Fasteris SA, Geneva, Switzerland Heinrich-Heine University, Research, Sleep Medicine Düsseldorf, Germany Bio-Rad Laboratories de Genève, Switzerland Laurent KELLER and Chronobiology (SGSSC) Philipp KHAITOVICH Claudio LOTTAZ UNIL, Lausanne, Switzerland Schüller-Stiftung Bucher Biotec Max Planck Institute for Max Planck Institute, Joëlle MICHAUD Evolutionary Anthropology, Swiss Academy of Sciences Illumina Berlin, Germany UNIL, Lausanne, Switzerland Leipzig, Germany Swiss National Science Life Systems Design Milos PJANIC Carlo RIVOLTA Jennifer MARSHALL GRAVES Foundation (SNSF) NuGEN Technologies EPFL / UNIL, Lausanne, UNIL / CHUV, Lausanne, Australian National University, Switzerland Switzerland Operon Biotechnologies Canberra, Australia Michael STADLER Daniel ROBYR John MORAN Quiagen FMI, Basel, Switzerland University of Geneva, Switzerland University of Michigan Roche Diagnostics Werner VAN BELLE David SHORE Ann Arbor, USA ETHZ, Zurich, Switzerland University of Geneva, Switzerland Starlab and BSSE, Basel, Switzerland Martin PARNISKE University of Munich, Germany Syngenta Daniel ZERBINO Tecan Wellcome Trust Sanger William RICE Institute, Cambridge, UK University of California, UCB Pharma Santa Barbara, USA Umetrics Eduardo ROCHA Institut Pasteur, Paris, France Witec AG

and the member companies of the KGF (Kontaktgruppe für Forschungsfragen): Novartis Hoffmann-La Roche Merck Serono

61 Education

The Cig Annual Retreat The Cig And The Public

The CIG organizes a yearly annual retreat where all CIG members, The CIG being a university department, its first teaching duties are whether students, postdoctoral fellows, professors and group of course to students and other members of the academic staff. leaders, or technicical and administrative staff, are invited. However, in a world where the development of knowledge and technology in biological sciences concerns each and everyone, the The retreat provides an opportunity for researchers to exchange on CIG considers it part of its mission to establish a link with the pub- their work progress and future plans, as each group presents an lic at large and to communicate with non-scientists. update of its research to the full Génopode scientific community in talks and poster sessions. In addition, faculty members prepare The CIG is particularly active in communication with children and presentations to introduce their work to non-scientific staff, and teenagers, tomorrow’s citizen and maybe tomorrow’s research- these efforts are greatly appreciated as they allow all CIG person- ers. The Center organizes every year visits within the framework of nel to take part in the excitement of scientific discovery. the “Passeports Vacances”, which organizes activities for children, during their holidays. It also welcomes children visiting with their The CIG annual retreat is also an unmatched opportunity for infor- schoolteachers. mal discussions between CIG members, and an opportunity for all to interact in a relaxed atmosphere. Anyone can come to the Center, visit the laboratories and discuss with the scientists during the UNIL open doors (les Mystères de The retreat was organized in 2007 and 2008 in Saas Fee, a beauti- l’UNIL) and on other occasions such as the “Jours du Gène”. ful location in the Swiss mountains. These activities are not only an opportunity to inform the public Prizes awarded about the research done at the CIG, but also a chance to inter- at the CIG annual act with non-scientists and discuss different research-related issues retreat raised in today’s society. For the scientists, and in particular for the PhD students and postdoctoral fellows, it is an opportunity to talk Marie FABLET with the general public about their work and to get experience in Group Kaessmann the communication of science to non-scientists, whether it be chil- Best poster 2007 dren, teenagers or adults. Overall, about a thousand members of the public at large visit the Christina HERTEL CIG each year on these different occasions. Groupe Herr Best poster 2008 see also: www.unil.ch/cig/page63732_en.html Communication to the public can take the form of press releases. The CIG issued 10 press releases on its research results, which were Gilles BOSS then featured by the local, national, and international media. Stéphane PORCHET CIG central services see also: www.unil.ch/cig/page16994.html UNIBAT Special poster prize

62 CIG 2007/2008 Artist In Residence At The Cig

As part of its activities with the public at large, the CIG collabo- rated in 2008 with the program “Artist-in-Labs” (AIL), a collabora- tion between the Zurich University of the Arts, Institute for Cul- tural Studies in the Arts ICS and the Bundesamt für Kultur BAK. AIL finances a nine month residency for an artist in a swiss research laboratory. Sylvia Hostettler, an artist from Bern with a background in sculp- ture, installation, and photography was thus integrated in the CIG laboratory of Prof. C.Fankhauser, a new experience for both the scientists and the artist. The result of this interaction is an instal- lation visible in the Génopode in 2009: “Dimensions of Apparent Invisibility”. see also: www.artistsinlabs.ch/english/index.htm www.unil.ch/cig/page63732.html www.sylviahostettler.ch/

Partners

For its activites directed at the public, the CIG collaborates with the public laboratory of the UNIL, l’Eprouvette, which is part of the UNIL Interface-Science and Society, and with UNICOM (the UNIL communication services).

63 People

France Diserens Animal keeper Wanda Dolci Technician Julien Postdoctoral fellow Catherine Morel* Technician Hélène Mottaz People Dorier* Civilian service Pieric Doriot* Masters student Stéphane Technician Norman Moullan Technician Lourdes Mounien Dorsaz PhD student Cécile Duléry* Technician Ilhem Elkochairi PhD Postdoctoral fellow Karim Nadra* Postdoctoral fellow Gergely Nagy The CIG activities and dynamism result not only from the work of student Martine Emery* Technician Yann Emmenegger Technician IT specialist Pipat Nawathean Postdoctoral fellow Jean-Marie the group leaders and faculty members, but in a large part from Marie Fablet* Postdoctoral fellow Christian Fankhauser Group Ndoumve Technician Virginie Nepote* Postdoctoral fellow Sophie the contributions of people in training: master- and graduate stu- leader Jérôme Feige* Postdoctoral fellow Vincent Fiechter* PhD Nicod Masters student Brigitte Notari Animal keeper Alexandra dents, and postdoctoral fellows. Laboratory technicians are key to student Ana Florencia Silbering Postdoctoral fellow Laurence Paillusson Technician Nataska Pernet Apprentice technician Emilie research, as is the other technical and administrative staff as well Flückiger Editorial assistant G&D Paul Franken Group leader Person Masters student Corinne Peter-Blanc Technician Marlène as all the people from the CIG and the UNIL who make it possible Christiane Freymond Technician He Fu PhD student Thierry Genoud* Petit Secretary Brice Petit Technician Corinne Pfister Technician for the researchers to do research and for the people in training Postdoctoral fellow Alan Gerber* Trainee Nele Gheldof Postdoctoral Virginie Philippe PhD student Lukasz Potrzebowski PhD student to learn. The CIG is currently composed of about 190 members fellow Darlene Goldstein* Bioinformatician Diego Gonzalez* Alexandra Potts Technician Carine Poussin* Bioinformatician Sylvain originating from 26 different countries on 5 continents. There are Masters student Patrick Gouait Animal facility responsible Marion Pradervand Bioinformatician Viviane Praz Bioinformatician 16 group leaders and faculty members, about 45 PhD students, Graf Apprentice technician Yaël Grosjean Postdoctoral fellow Alain Manfredo Quadroni Core facility coordinator Laure Quignodon 1 50 postdoctoral fellows, 50 specialists and laboratory technicians Guéniot Animal keeper Sophie Guernier PhD student Laure Gurcel* Postdoctoral fellow Yann Ravussin* PhD student Caroline Ravy 1 (including trainees), and 25 persons employed in the administra- Postdoctoral fellow Joël Gyger* Technician Otto Hagenbüchle Core Animal keeper apprentice Michael Reid Postdoctoral fellow Jaime tive and the logistic services (including trainees). facility specialist Matthew Hall PhD student Diana Hall Postdoctoral Humberto Reina PhD student Marianne Renaud Masters student/ 1many members of the support staff work part-time. fellow Corinne Hänggeli IT specialist Louise Harewood Postdoctoral PhD student Alexandre Reymond Group leader Guénola Ricard fellow Keith Harshman Core facility coordinator Subah Hasan* PhD Postdoctoral fellow Hannes Richter Core facility specialist Aurélie Jean-Paul Abbuehl* Technician Liliane Abuin Technician Ildiko student Vanessa Hassler* Apprentice secretary Katharina Hausherr Righetti Masters student Cylia Rochat* Student trainee Sara Agoston* Stocks and ordering office Imtiyaz Ahmad* PhD student Technician Christophe Héligon Postdoctoral fellow Charlotte Rodriguez-Jato Postdoctoral fellow Catherine Roger Technician Lia Emilie Aït Yahya Graison Postdoctoral fellow Monica Albarca PhD Henrichsen PhD student Nouria Hernandez Group leader Celine Rosso Postdoctoral fellow Nicolas Rotman Maître assistant Jézaëlle student Laure Allenbach Technician Silvia Anghel* PhD student Hernandez Bioinformatician Winship Herr Group leader Christina Rufener Animal keeper apprentice Raphaël Rytz PhD student Teldja Neige Azzouz* Postdoctoral fellow Isabelle Bady* Postdoctoral Hertel Postdoctoral fellow Valérie Hinard Postdoctoral fellow Audrey Sambeat PhD student Hitomi Sanno Postdoctoral fellow fellow Jachen Barblan Technician David Barras* Masters student Wassim Hodroj Postdoctoral fellow Hyun Hor Postdoctoral fellow Chiara Sardella Trainee Fabienne Sauvain Secretary Isabelle Michaël Baruchet Masters student Armelle Bauduret Technician Virginie Horn Postdoctoral fellow Patricia Hornitschek PhD student Schepens* Postdoctoral fellow Fabian Schweizer* Masters student Emmanuel Beaudoing Bioinformatician Elodie Bedu* Postdoctoral Sylvia Hostettler* Artist in residence Cédric Howald PhD student Pascal Seyer Postdoctoral fellow Magali Soumillon PhD student fellow Rati Bell PhD student Felipe Bendezú Postdoctoral fellow Henrietta Hrobova Crausaz* Masters student José Luis Huaman Jérôme Soyer Animal keeper Andrzej Stasiak Group leader Alicja Richard Benton Group leader Marlyne Berger Stocks and ordering Larios Animal keeper Maude Husson Technician José Iglésias PhD Stasiak Technician Mehdi Tafti Group leader Corinne Tallichet-Blanc office Claire Bertelli* Masters student Martine Berthelot-Grosjean student Maxwelll Ingman* Postdoctoral fellow Nicole James Faresse Technician David Tarussio Technician Zofia Terreau-Haftek* Technician Béatrice Bordier* Technician Gilles Boss Technician David Postdoctoral fellow Maria Jimenez Postdoctoral fellow Sonia Postdoctoral fellow Raphaël Terrier PhD student Gnanasekaran Brawand PhD student Jean-Marc Brunner PhD student Diane Jimenez Technician Magali Joffraud Technician Philippe Julien PhD Thoppae Bioinformatician Bernard Thorens Group leader Sajit Buczynski-Ruchonnet Postdoctoral fellow Manuel Bueno* student Fabienne Junod Fontolliet Animal keeper Henrik Thottathil Oomment PhD student Momirka Trenkoska-Olmo* Technician Yannis Burnier* Civilian service Donatella Canella Kaessmann Group leader Chitose Kami Postdoctoral fellow Philippe Animal keeper Martine Trevisan Technician Ana Tufegjzic* Student Postdoctoral fellow Danielle Canepa Del Canto-Perri Secretary Kircher Apprentice technician Sonia Klinger* PhD student Jacqueline trainee Shweta Tyagi Postdoctoral fellow David Vallois Postdoctoral Francesca Capotosti PhD student Marianne Carrard Technician Kocher Braissant Technician Kyriakos Kokkoris PhD student Radina fellow Frédéric Varnat* Postdoctoral fellow Anne Vassalli Cristina Casals Casas Postdoctoral fellow Daniel Catalano Animal Kostadinova* Postdoctoral fellow Alexandra Krauskopf* Postdoctoral fellow Angélique Vaucher Apprentice technician Julie keeper Evelyne Chaignat PhD student Jean-Vincent Chamary* Postdoctoral fellow Philippe L’Hôte Technician Francesco La Spada* Vienne PhD student Erwann Vieu Maître assistant Nicolas Postdoctoral fellow Pei-Jiun Chen Postdoctoral fellow Jacqueline Masters student/PhD student Frédéric Laurent* Masters student Vinckenbosch PhD student/Postdoctoral fellow Camille Volz Chrast Technician Nathalie Clerc Secretary Sara Coleman Summer Alexandra Laverrière PhD student Helen Lennox Editorial assistant Apprentice secretary Nicole Vouilloz Assistant director Laurie Vuillet student Mara Colzani PhD student Aurélie Comte* Student trainee G&D Nicolas Leuenberger PhD student Séverine Lorrain Postdoctoral Postdoctoral fellow Vanja Vukojevic Summer student Walter Wahli Floriane Consales Technician Nathalie Constantin Research support fellow Lionel Maquelin* Masters student Andrea Maran* Masters Group leader Fang Wang Summer student Zhenghui Wang* Trainee Marion Cornu PhD student Pascal Cousin Technician Annick student Fabrice Marcillac* Postdoctoral fellow Stéphanie Maret* Patrice Waridel Core facility specialist Marta Wawrzyniak PhD Crevoisier Secretary Vincent Croset Masters student Thomas Curie PhD student, Postdoctoral fellow Ana Marques* PhD student student Johann Weber Core facility specialist Manuela Weier Postdoctoral fellow Nicolas Damont* Masters student Cynthia Sophie Martin Group leader Nell Marty* PhD student Matthieu Technician Elisabeth Weiler Washing facility Sophie Wicker Dayer* Masters student Matthieu De Carbonnel PhD student Membrez* Postdoctoral fellow Fabienne Messerli Technician Technician Deborah Widmer Masters student Bartosz Wierzbicki Dimitry Debrieux PhD student Marie-Bernard Debril* Postdoctoral Geneviève Metthez* Technician Liliane Michalik Group leader Joëlle Apprentice technician Gilles Willemin* Masters student Carine fellow Sébastien Del Rizzo* Masters student Muriel Delestre-Cartier* Michaud Postdoctoral fellow Annemieke Michels Postdoctoral Winkler Technician Robert Witwicki PhD student Guillaume Witz* Editorial assistant G&D Emilie Demarsy Postdoctoral fellow Davide fellow Kaori Minehira Postdoctoral fellow Jovan Mircetic* Summer Civilian service Nicolai Wohns Student trainee Céline Wyser Demurtas PhD student Corinne Dentan Secretary Béatrice student Honey Modi PhD student Valérie Mongrain Postdoctoral Apprentice technician Yanfang Ye Postdoctoral fellow Zhou Zhou* Desvergne Group leader Gérard Didelot Postdoctoral fellow Marie- fellow Alexandra Montagner Postdoctoral fellow Mauro Montanaro Student trainee Cynthia Zimmermann Washing facility *left the CIG

64 CIG 2007/2008 Faculté de biologie et de médecine CIG – Centre Intégratif de Génomique | UNIL-Université de Lausanne Bâtiment Génopode | CH-1015 Lausanne | Switzerland | Tél. ++41 (0)21 692 39 00

www.unil.ch/cig