The Center for Integrative Genomics Report 2005–2006

The Center for integrative genomics Report 2005–2006

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Presentation

Director’s message 4 Scientific advisory committee 6 Organigram of the CIG 7 Research

The structure and function of genomes and their evolution Alexandre Reymond – Genome structure and expression 10 Henrik Kaessmann – Evolutionary genomics 12 Victor Jongeneel – Cancer genomics 14 The regulation of gene expression Nouria Hernandez – Mechanisms of transcription regulation 16 Winship Herr – Regulation of cell proliferation 18 Christian Fankhauser – Light–regulated development in plants 20 The genomics of complex functions Mehdi Tafti – Genetics of sleep and the sleep EEG 22 Paul Franken – Genetics and energetics of sleep homeostasis and circadian rythms 24 Walter Wahli – Peroxisome Proliferator–Activated Receptors (PPARs) as regulators of metabolic and tissue repair processes 26 Béatrice Desvergne – PPARbeta and fine tuning of cell fate decision 30 Liliane Michalik – Roles of PPARs in skin biology and angiogenesis 34 Bernard Thorens – Molecular and physiological analysis of energy homeostasis in health and disease 36 Core facilities

Core facilities of the CIG 39 DNA array facility – DAF 40 Protein analysis facility – PAF 42 Core facilities associated with the CIG 44 Education

Lectures and courses 48 Seminars at the CIG 51 CIG retreat 56 The CIG & the public 56 Funding (Acknowledgements) 58 People 59 CIG Timeline

CIG Timeline

Inauguration of the Pro- tein Analysis Facility (PAF – December 2002)

Inauguration of the DNA Array Facility (DAF – March 2003)

Arrival of Prof. Kaessmann (September 2003)

Installation Arrival of of Vital–IT Prof. Thorens in the Génopode (October 2003)

Arrival of Inauguration of the Prof. Hernandez The construction of Prof. Hernandez, Cellular Imaging Facility becomes the second the big animal facility Herr and Tafti at the Génopode CIG director is rejected by popular (September 2004) referendum

Arrival of Arrival of Arrival Arrival Inauguration First CIG retreat Prof. Reymond Prof. Fankhauser of Dr. Franken of Prof. Desvergne, of the CIG in Saas Fee (October 2004) Wahli and Dr. Michalik

01 02 03 04 05 06 07 08 09 10 11 12 2003 2004 2005

CIG 2005/2006 Installation HeLa in the «Journées de «passeports vacances» Lectures Inauguration of the hall of the Génopode la recherche en (July and August) «continuing Center for Investigation (until December 2006) génétique» education» and Research on Sleep (CIRS)

UNIL Second CIG Installation of the Mouse open house days retreat in Metabolic Evaluation Saas Fee Facility (MEF)

01 02 03 04 05 06 07 08 09 10 11 12 2007 2006

Presentation | Message from the Director

Message from the Director

We are in the midst of a first Faculty of Biology and Medicine in Switzerland. It also resulted in her knowledge of mouse work to help in the design of the CIG ani- revolution in the biological the creation of two research axes, one focused on functional genomics mal house. The renovation was officially completed in May 2005, and sciences. and the other on human and social sciences. the last group to move in, that of Bernard Thorens, arrived in October 2005, just in time for the inauguration! This revolution, started with the sequen- What form the functional genomics axis of the SVS program would cing of the human genome and then that take was of great interest to W. Wahli (UNIL) and D. Duboule (UNIGE) After several years of relentless work to see the CIG evolve from an of a number of other organisms, conti- who composed, as early as 1999, a first document describing a “Swiss idea, formulated in early 1999, to a reality, Walter Wahli resigned as nues with the spectacular development of Center of Genetics/Genomics”. The missions of this proposed center CIG Director as of September 2005, having decided, I think, that it was technologies that allow the interrogation included cutting–edge research and teaching in genomics, data collec- time for the CIG to “fly with its own wings”, and that it was time for of thousands of molecules in one experiment. We can now not only tion and analysis, the development of core facilities, the development him to go back to teaching and research. We at the CIG are all indeb- compare the genome structures of, for example, a normal cell and a of interactions between fundamental and biomedical research, and the ted to Walter and it is fitting that he be thanked here, in this first bien- cancer cell, but also the expression pattern of an entire genome in dif- facilitation of technology transfer, an ambitious set of goals indeed! nial report of CIG, for having devoted so much effort and energy to the ferent cells, at different times, and under different conditions. Any mo- development of this very unique center! And on my part, I thank him lecule of interest can be analyzed in such a global manner, from mRNAs, In the following year, the project was further studied by two com- for having helped immensely the next CIG director learn the ropes! small RNAs, and proteins to metabolites and other compounds. The mittees, the “groupe de réflexion stratégique lausannois” on the one techniques that allow these types of experiments are powerful, but hand, and a group of three people representing the three SVS pro- The CIG inauguration was closely followed by the success of the popu- they offer a challenge to the individual research laboratory: they rely gram institutions and charged with developing its genomic aspect on lar referendum against the construction of a large animal house, the on costly instruments, unaffordable for the typical research group, and the other hand. These documents already mentioned the Center by its last piece of the CIG project, that was to be built underground on the on highly specialized know–how, and this not only for the generation present name, the Center for Integrative Genomics, and mentioned its south side of the Génopode. This was indeed a depressing moment for of the data but also for their analysis. location in the Pharmacy Building of the UNIL. The CIG was viewed the just inaugurated CIG and was to have profound long–term conse- as a place where genetic models then absent at the UNIL would be quences for the UNIL at large, all of which have yet to be fully grasped. It is in the context of this biological revolution that the Center for Inte- introduced, where bioinformatics would be developed, and where core One consequence was the impossibility for the CIG to develop further grative Genomics was created, a center combining research groups facilities would be established. The second document described the research using the mouse as an animal model, and another was the working on functional genomics with core facilities offering, not only CIG as a new type of structure, perhaps a foundation, co–owned by greatly increased difficulty to regroup basic research on the Dorigny to the Center itself but to the entire surrounding region, the latest tech- the three SVS members. campus. It is with these new elements that the CIG completed its first nologies in genome analyses. The Center was officially inaugurated on year in the Génopode. the 27th of October 2005. The inauguration was followed on the 28th In 2001, a final report was presented to the Rectorate of the UNIL by a by the inaugural CIG Symposium “Genomics, a new road for science group composed of professors from the Faculty of Sciences and from With all its groups now in a single building, the CIG could start taking and society”. These public events that marked the birth of the CIG the Faculty of Medicine. One of the important points of this report was care of recruiting new colleagues. One of the first undertakings was were the culmination of an enormous amount of work that involved the realization that the financing of the CIG, originally imagined as pro- the organization, in large part through the efforts of C. Fankhauser, many scientists in the Lemanic region. vided by the three SVS institutions, would in fact be provided by the A. Reymond, and B. Thorens, of a seminar series in which we invited a UNIL; this led to the eventual incorporation of the CIG into the UNIL as number of young people eligible to apply for a “professeur boursier” The conception of the CIG was intimately linked to the project “Sci- a department of its Faculty of Biology and Medicine. position to present their work and meet CIG faculty. A few months ence, Vie, Société” (SVS), in which, in an unprecedented collaborative after this recruitment effort, a second recruitment was launched to fill effort, the Universities of Lausanne (UNIL) and Geneva (UNIGE), and In 2002, Walter Wahli was appointed the founding director of the CIG, our last CIG faculty position. The recruiting committee included profes- the EPFL (Ecole Polytechnique Fédérale de Lausanne) agreed to redis- and in Autumn 2004, work started in the building now known as the sors S. Antonarakis (UNIGE), M. Swartz (EPFL), J. Beckmann, L. Keller, tribute some of their competences to avoid redundancies and optimize Génopode to prepare it for the move of the first CIG groups. Several P. Moreillon, J. Tschopp, and myself, as well as M. Haenni who re- the use of resources. The SVS project was developed in the years 2000 people gave a lot of their time to the transformation of the Pharma- presented the “corps intermédiaire” and L. Baratali who represented and 2001 and resulted in the transfer of the UNIL sections of Che- cy Building into the Génopode, in particular Liliane Michalik, the de- the students (all UNIL). The committee was presided by I. Stamenko- mistry, Mathematics, and Physics to the EPFL, in the fusion of the UNIL legate of the Rectorate to the renovation of the building, who worked vic (UNIL). Thanks to the enthusiasm and energy of its president and School of Pharmacy with that of the UNIGE, and in the fusion of the closely with the architect Guido Cocchi and with the coordinator of the the dedication of committee members, progress was fast. As a result UNIL Biology section with the UNIL Faculty of Medicine to create the work on the site, Stéphane Porchet. Béatrice Desvergne contributed of these combined efforts, by the end of 2006 the CIG had recruited

CIG 2005/2006 Landmarks of the development of the Center for Integrative Genomics

The Science, Vie, société (SVS) program The CIG a candidate professeur boursier, Dr. Sophie Martin, and an assistant professor, Dr. Richard Benton. Sophie Martin is presently a post–doc- • 22–10–1998: first outline of a tripartite (UNIL, UNIGE, EPFL) toral fellow in the Department of Microbiology at Columbia Univer- coordination project sity in New York, USA, working with Fred Chang on cell polarization in the fission yeast Schizosaccharomyces pombe. Richard Benton is a post–doctoral fellow at the Rockefeller University in New York, USA, • Spring 1999: W. Wahli and D. Duboule author a first docu- working with Dr. Leslie Vosshall on olfaction in the fruit fly, Drosophila ment describing a “Swiss Center of Genetics/Genomics” melanogaster. We look forward to welcoming them in 2007! • 22–02–2000: founding document describing the SVS project Another type of recruiting effort was that of the CIG scientific advisory committee. We were fortunate to convince a group of exceptional scientists to be part of this committee; their guidance will be invaluable in • 16–08–2000: the “groupe de réflexion stratégique lausan- helping us achieve our missions. Their first visit will take place in June nois”, chaired by H. Diggelmann and composed of M. Aguet, of 2007 and they should find a fully functional CIG! J. Dubochet, L. Keller, N. Mermod, G. Pantaleo, B. Rossier, presents a report entitled “Centre intégratif de génomique et The CIG cannot easily be dissociated from the other “inhabitants” of pôle de génomique fonctionnelle” to the Rector of the UNIL. the Génopode building. The Génopode with all its research groups, including not only the CIG and the Unité CIG Sciences (UCS) but also groups from the Swiss Institute of Bioinformatics, the Ludwig Institute, • 30–06–2000: the cantons of Vaud and Geneva as well as the and the group of Olivier Michielin from the Multidisciplinary Oncolo- Swiss Confederation sign a common declaration of intent. gy Center (CePO), and with its core facilities including the DNA Array and Protein Analysis Facilities (DAF and PAF), the Cellular Imaging Faci- • 25–11–2000: H. Diggelmann (UNIL), D. Duboule (UNIGE), and lity (CIF), the Vital-IT facility, the Mouse Metabolic Evaluation Facility H. Vogel (EPFL) write a document titled “Pôle de génomique (MEF), is well prepared for the challenges of modern biology. The high- fonctionnelle”. ly interactive environment of the Génopode, together with its location on the Dorigny campus, close to its SVS partners, indeed neighbor to • 08–06–2001: report on the CIG to the UNIL Rectorate by N. the EPFL, and less than an hour away from the University of Geneva, Mermod, J. Dubochet, B. Desvergne, L. Keller, P. Mangin, J.P. makes it an exciting place to work. Kraehenbuhl, M. Aguet and G. Pantaleo.

The genomic revolution, with its new tools and the knowledge of entire genome sequences, is greatly accelerating the rapidity with which we • 03–07–2001: the Universities of Lausanne and Geneva, can decipher the mechanisms of life. The magnitude and speed of bio- and the EPFL sign the SVS convention. logical research today are having an ever increasing impact on society. Given the individuals involved and given the facilities available, there is • 01–01–2002: W. Wahli is appointed founding director no doubt in my mind that the CIG will develop into a major player in of the CIG international biology research. It will be all the more important, then, that it develops its mission of education and teaching, not only of stu- • 01–09–2005: N. Hernandez becomes 2nd CIG director dents in biology, but also of the public at large. • 27–10–2005: CIG inauguration Nouria Hernandez, Director • 28–10–2005: inaugural CIG symposium

Presentation | CIG – Scientific Advisory Committee

CIG – Scientific Advisory Committee

The CIG Scientific Advisory Committee (SAC) is a consultative commis- Dr Laurent DURET Prof. Ueli SCHIBLER sion of external experts widely recognized for their contribution in the Laboratory of Biometry and Member of the National Center fields of activity of the CIG. Its principal responsibilities are : Evolutionary Biology of Competence in Research Université Claude Frontiers in Genetics Bernard – Lyon I Department of Molecular Biology Villeurbanne, France University of Geneva • To advise on scientific objectives and priorities Geneva, Switzerland Prof. Robert EISENMAN • To evaluate the outcomes Fred Hutchinson Cancer Research Prof. Ivan STAMENKOVIC Center Director, Department of Experi- • To propose means of improving outcomes and visibility Department of Biochemistry mental Pathology University of Washington University of Lausanne • To propose the acquisition of new technologies or the development Seattle, USA Lausanne, Switzerland of new research and educational activities or services Prof. Susan GASSER Prof. Markus STOFFEL Director, Friedrich Miescher Institute of Molecular Systems The SAC will meet for the first time in June 2007 at the CIG. Institute for Biomedical Research Biology (FMI) Swiss Federal Institute of The CIG is particularly honored that the following persons accepted to Basel, Switzerland Technology Zurich (ETHZ) join the committee: Zurich, Switzerland Prof. Ueli GROSSNIKLAUS Department of Developmental Prof. Gisou VAN DER GOOT Genetics Global Health Institute University of Zurich EPFL (Ecole Polytechnique Zurich, Switzerland Fédérale de Lausanne) Lausanne, Switzerland Prof. Jacques SAMARUT Director of the research, Ecole Normale Supérieure (ENS) de Lyon Laboratory of Molecular Cell Biology Lyon, France and Université Claude Bernard Lyon I Villeurbanne, France

CIG 2005/2006 Organigram of the CIG Scientific Advisory Committee

University of Lausanne, Faculty of Biology and Medicine

Center for Integrative Genomics • Director: Nouria Hernandez Directing Committee: CIG faculty members, representative of the administrative and technical staff

Research Core Facilities

CIG Associated CIG Core Associated Core research groups research groups Facilities Facilities

• The structure and function of genomes and their evolution • DNA Array Facility – DAF • Vital-IT Alexandre Reymond / Henrik Kaessmann / Victor Jongeneel • Protein Analysis Facility – PAF • Cellular imaging facility – CIF • Bioinformatics core facility – BCF • The regulation of gene expression • Mouse metabolic evaluation facility – MEF Nouria Hernandez / Winship Herr / Christian Fankhauser • Centre for Investigation and Research on • The genomics of complex functions Sleep – CIRS Mehdi Tafti / Paul Franken / Bernard Thorens / Walter Wahli / Liliane Michalik / Béatrice Desvergne

Central Services

• Central administration • Common equipment lab • Animal facility • Washing facility • Genotyping • Workshop • Phenotyping • Informatic support • Sequencing • Stocks and ordering

Research research | The structure and function of genomes and their evolution alexandre reymond Genome structure and expression Group publications Assistant Professor

The completion of the human genome sequence, as well as recent Group leader researCh arTICles technological advances have demonstrated that our genome is much Alexandre Reymond more fl uid than we had thought and that variations can be of any scale. [email protected] eyras e, reymond a, castelo Inversions and copy number polymorphisms (CNPs), i.e. large stretch- r, Bye JM, camara F, Flicek P, es of genomic DNA that vary considerably in copy number, appear so TeChnICIan elizabeth J, huckle eJ, Parra abundant that it is conceivable that they play a major role in functional Jacqueline Chrast g, shteynberg DD, Wyss c, variation. Consistently, genomic insertions and deletions were shown rogers J, antonarakis se, to contribute to phenotypic differences by modifying the expression le- posTdoCToral felloWs Birney e, guigo r, Brent Mr vels of genes within the aneuploid segments. We have recently shown Gérard Didelot (2005) that not only the genes mapping within the microdeletion that causes Louise Harewood Gene fi nding in the chicken Williams–Beuren Syndrome (WBS), but also that the 7q11.23 normal genome. BMC Bioinformatics copy neighboring genes showed decreased relative levels of expres- phd sTudenTs 6 : 131 sion. Our results suggest that not only the aneuploid genes, but also Charlotte Henrichsen the fl anking genes that map several megabases away from a geno- Evelyne Chaignat Wattenhofer M, reymond a, mic rearrangement should be considered as possible contributors to Cédric Howald Falciola V, charollais a, caille the phenotypic variation in genomic disorders. Thus we can hypoth- D, Borel c, Lyle r, estivill X, esize that changes in genome structure will modify the phenotype not admInIsTraTIve Petersen MB, Meda P, anto- only by changing levels of expression of genes mapping within the assIsTanT narakis se (2005) rearranged region, but also of genes mapping nearby. We will test this Annick Crevoisier Different mechanisms preclude hypothesis by measuring relative expression levels of these genes (i) in mutant CLDN14 proteins to form cell lines without or with a rearrangement, namely recurrent deletions, tight junctions in vitro. Hum balanced translocations and inversions; and (ii) in mouse tissues with Mutat 25 : 543–549 varying copy numbers of CNPs. This should allow better understanding on how large size variation are infl uencing the expression genes and castelo r, reymond a, Wyss possibly the phenotype. c, camara F, Parra g, antonarakis se, guigó r, eyras e (2005) Comparative gene fi nding in Alexandre Reymond carried out his thesis in the laboratory of Dr. Vies- chicken indicates that we are clo- turs Simanis at the Swiss Institute for Experimental Cancer Research sing in on the human gene set. (ISREC) and received his PhD from the University of Lausanne in 1993. Nucleic Acids Res 33 : 1935–1939 After completion of his postdoctoral training with Dr. Roger Brent in the Department of Molecular Biology, Massachusetts General Hospital Wattenhofer M, sahin–ca- and in the Department of Genetics, Harvard Medical School in Bos- lapoglu n, andreasen D, ton, USA, he moved to the Telethon Institute of Genetics and Medicine Kalay e, caylan r, Braillard B, (TIGEM) in Milan, Italy, in 1998 to lead a research group. He joined in Fowler–Jaeger n, reymond 2000 the Department of Genetic Medicine and Development, Univer- a, rossier Bc, Karaguzel a, sity of Geneva Medical School. He moved to the Center for Integrative antonarakis se (2005) Genomics in October 2004.

10 cig 2005/2006 Collaborations

A novel TMPRSS3 missense ploidies identify new Williams– S, Hubbard T, Reese MG Dermitzakis ET, Reymond A S. E. Antonarakis, mutation in a DFNB8/10 family Beuren Syndrome patients with (2006) (2005) University of Geneva, Switzerland prevents proteolytic activation atypical deletions. J Med Genet EGASP : the human ENCODE DNA sequence evolution and A. Ballabio, of the protein. Hum Genet 117 : 43 : 266–273 Genome Annotation ASsessment phylogenetic footprinting. In : Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy 528–535 Project. Genome Biol 7 Suppl 1 : Mammalian Genomics; Ruvinsky Parra G, Reymond A, Dab- S2 1–31 A and Marshall Graves JA eds; E. Birney, Bonafé L, Dermitzakis ET, bouseh N, Dermitzakis ET, CAB International, UK European Bioinformatics Institute, Hinxton, UK Unger S, Greenberg C, Xavier Antonarakis SE, Thomson TM, Merla G, Howald C, Henrich- E. Blennow, B, Zankl A, Ucla C, Antona- Guigó R (2006) sen CN, Lyle R, Wyss C, Zabot Deutsch S, Reymond A (2006) Karolinska University Hospital Solna, Stockholm, Sweden rakis SE, Superti–Furga A, Tandem chimerism as a mean MT, Antonarakis SE, Reymond Meeting report : The future is ge- Reymond A (2005) to increase protein complexity A (2006) nome–wide. Genome Biol 7 : 324 H. G. Brunner, Evolutionary comparison provide in the human genome. Genome Submicroscopic deletion in Stichting Katholieke Universiteit, Nijmegen, Netherlands S. Eliez, evidence for pathogenicity of Res 16 : 37–44 patients with Williams–Beuren Deutsch S, Antonarakis SE, University of Geneva, Switzerland RMRP mutations. PLoS Ge- syndrome influences expression Reymond A (2006) D. FitzPatrick, net 1 : e47 Drake JA, Bird C, Nemesh J, levels of the nonhemizygous Disorders of chromosome 21. Medical Research Council (MRC), Edinburgh, UK Thomas D, Newton–Cheh C, flanking genes. Am J Hum Genet In : Encyclopedic Reference of Mehenni H, Lin–Marq N, Reymond A, Excoffier L, Attar 79 : 332–341 Genomics and Proteomics in Mo- T. E. Gingeras, Buchet–Poyau K, Reymond A, H, Antonarakis SE, Dermitza- lecular Medicine; Ganten D and Affymetrix Inc., Santa Clara, USA Collart MA, Picard D, Antona- kis ET, Hirschhorn JN (2006) review article Ruckpaul K eds; Springer Verlag, rakis SE (2005) Conserved non–coding sequen- Berlin Heidelberg & New York R. Guigo, Centre de Regulació Genomica, Barcelona, Spain LKB1 interacts with and phos- ces are selectively constrained Dermitzakis ET, Reymond A, phorylates PTEN- a functional and not mutation cold spots. Antonarakis SE (2005) J. Harrow and T. Hubbard, link between two proteins Nature Genet 38 : 223–227 Conserved non–genic sequen- Wellcome Trust Sanger Institut, Hinxton, UK involved in cancer predisposing ces – an unexpected feature of syndromes. Hum Mol Genet 14 : Harrow* J, Denoeud* F, Fran- mammalian genomes. Nat Rev Y. Herault, 2209–2219 kish* A, Reymond* A, Chen Genet 6 : 151–157 CNRS, Orléans, France CK, Chrast J, Lagarde J, Gil- M. del Mar Dierssen Soto and X. Estivill, Marques AC, Dupanloup I, bert JGR, Storey R, Swarbreck Letters to the editor, Centre de Regulació Genomica, Barcelona, Spain Vinckenbosch N, Reymond A, D, Ucla C, Hubbard T, Antona- Book chapters Kaessmann H (2005) rakis SE, Guigó R (2006) G. Merla, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy Emergence of young human ge- GENCODE : Producing a refe- Antonarakis SE, Reymond A, nes after a burst of retroposition rence annotation for ENCODE. Menzel O, Bekkeheien R, Fu- L. Pérez Jurado, in primates. PLoS Biol 3 : e357 Genome Biol 7 Suppl 1 : S4 1–9 kai N, Kosztolanyi G, Aftimos Universitat Pompeu Fabra, Barcelona, Spain *equal author contribution S, Deutsch S, Scott HS, Olsen Howald C, Merla G, Digi- BJ, Guipponi M (2005) M. Ruedi, lio MC, Amenta S, Lyle R, Guigó R, Flicek P, Abril JF, A response to Suzuki et al, “How Muséum d’Histoire Naturelle, Geneva, Switzerland Deutsch S, Choudhury U, Reymond A, Lagarde J, pathogenic is the p,D104N/en- M.–L. Yaspo, Bottani A, Antonarakis SE, Denoeud F, Antonarakis SE, dostatin polymorphic allele of Max Planck Institute for Molecular Genetics Berlin, Germany Fryssira H, Dallapiccola B, Ashburner M, Bajic VB, Birney COL18A1 in Knobloch syndro- Reymond A (2006) E, Castelo R, Eyras E, Gingeras me ?”. Hum Mutat 25 : 316 M.–T. Zabot, Two high–throughput technolo- TR, Good P, Harrow J, Lewis Hôpital Debrousse, Lyon, France gies to detect segmental aneu-

11 Research | The structure and function of genomes and their evolution

Henrik Kaessmann Evolutionary Genomics Assistant Professor

The research of my group focuses on the origin and evolution of In addition to these major lines of research, we have been collaborating new genes (and gene structures) that emerged recently on the pri- with several groups at the University of Lausanne and abroad to work mate lineage leading to humans from duplicate gene copies. We on various projects pertaining to molecular evolution, such as the evo- have in particular focused on the origin of new genes by retroposi- lution of viral host defense genes (with A. Telenti, Centre Hospitalier tion (or retroduplication), where the mRNA of a parental source gene is Universitaire Vaudois (CHUV) and University of Lausanne), or the evo- reverse–transcribed and integrated into a new genomic position (medi- lutionary fate of egg yolk genes in mammals (with W. Wahli, CIG). ated by enzymes derived from L1 retrotransposable elements), gene- rating intronless retrocopies of the parent. We showed that retroduplication has generated a significant number of functional retrogenes on the primate lineage leading to humans, about one new retrogene per million years during primate evolution. To understand the source of regulatory elements of retrogenes that allows for their functiona- lity, we systematically studied retrocopy transcription. We found that retrocopies often profit from the transcription of nearby genes, either by directly utilizing the transcriptional machinery of host genes (e.g. by gene fusion), or by profiting from cis–acting regulatory elements and/ or open chromatin of nearby genes.

In a systematic evolutionary survey of primate retrocopies, we pinpoin- ted several functional human retrogenes that emerged between ~18 to ~35 million years ago. In addition to showing a more tissue–specific expression pattern, several of these young retrogenes displayed signa- tures of positive selection, indicative of new or modified protein functions. With respect to their spatial expression patterns, we found that, generally, these retrogenes revealed a testis expression bias, which is probably due to the generally promiscuous transcription of chromatin in late male meiosis. This initially mechanistically–driven transcription may have allowed retrocopies to often initially evolve into retrogenes Henrik Kaessmann received his PhD in 2001 from the University of with functions in testis. However, later in their evolution they may Leipzig, after working on the genetic diversity of humans and the evolve functions in other tissues. Indeed, we have discovered and cha- great apes in the laboratory of Dr. Svante Pääbo at the University of racterized several intriguing brain–expressed retrogenes (e.g. GLUD2 Munich and subsequently at the Max Planck Institute for Evolutionary and CDC14Bretro) that originated recently in the hominoid ancestor, Anthropology, Leipzig, Germany. He obtained his postdoctoral training experienced intense positive selection, and may thus have contributed with Dr. Wen–Hsiung Li in the Department of Ecology and Evolution to the evolution of the more complex human brain. at the University of Chicago, USA, where he worked on the origin of human genes and gene structures. He joined the Center for Integrative We are currently expanding our work on duplicate genes to study the Genomics in 2003. evolution and phenotypic impact of very recent (and hence polymorphic) human and chimpanzee genes contained within duplicated chromosomal segments (so called segmental duplications).

12 CIG 2005/2006 Group Publications Collaborations

GROUP LEADER Research articles S. Bahn, Henrik Kaessmann Centre for Neuropsychiatric Research, Cambridge, UK [email protected] Marques A*, Dupanloup I*, L. Hurst, Vinckenbosch N, Reymond A, University of Bath, UK TECHNICIAN Kaessmann H (2005) Manuela Weier Emergence of young human ge- L. Keller and R. Hammond, nes after a burst of retroposition University of Lausanne, Switzerland POSTDOCTORAL FELLOWS in primates. PLoS Biol 3 : e357 S. Pääbo, Jean–Vincent Chamary *equal author contribution Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany Isabelle Dupanloup* Maxwell Ingman Dupanloup I, Kaessmann H A. Telenti, Lia Rosso (2006) Centre Hospitalier Universitaire (CHUV) and University of Lausanne, Switzerland Evolutionary simulations to W. Wahli, PhD STUDENTS detect functional lineage–spe- University of Lausanne, Switzerland David Brawand cific genes. Bioinformatics 22 : Ana Machado Rebelo Marques 1815–1822 Lukasz Potrzebowski Nicolas Vinckenbosch Vinckenbosch N, Dupanloup I, Lionel Maquelin Kaessmann H (2006) Evolutionary fate of retroposed MASTER STUDENT gene copies in the human Lionel Maquelin* genome. Proc Natl Acad Sci USA 103 : 3220–3225 ADMINISTRATIVE ASSISTANT Ortiz M, Bleiber G, Martinez Annick Crevoisier R, Kaessmann H, Telenti A (2006) *left the group Patterns of evolution of host proteins involved in retroviral pa- thogenesis. Retrovirology 3 : 11

13 Research | The structure and function of genomes and their evolution

Victor Jongeneel Cancer genomics Associate professor ad personam

Recent evolution of genes coding for cancer–testis (CT) antigens: We tome (tagger and fetchGW), and derivation of detailed gene models are comparing the sequence, structure and chromosomal localization with alternative splicing from a collection of cDNA to genome align- of CT antigens between the chimpanzee and human genomes. Our ments (tromer). We are in the process of benchmarking these pro- data show that as expected, the human and chimpanzee CT gene grams against other publicly available software and of documenting families are found in the same genomic neighborhoods. However, it them in detail. is clear that CT genes, both on the X chromosome and on autosomes, are under strong diversifying selection, as witnessed by high non–sy- nonymous substitution rates and hominid–specific gene duplications. In fact, CT genes account for much of the excess positive selection observed on the X chromosome relative to autosomes.

Establishing a comprehensive catalog of human X–linked CT genes: The literature on CT–X genes is rather fragmented, with inconsistent nomenclatures and often inconclusive data to support the classifica- tion and inventory of gene families. We are in the process of trying to establish a “definitive” catalog of CT–X genes, with the aim to publish an authoritative review on the subject.

Identification of novel tumor antigens in colon carcinomas: Using MPSS and EST data, we have identified several new genes that are differen- tially expressed in colon carcinomas relative to normal colon epithelium. Their differential expression has been verified by Q–PCR on multiple tumor biopsies. Their potential as targets for immunotherapy is currently being investigated.

Analysis of the mouse reference transcriptome: Several Institutes within the NIH have commissioned the production of an in–depth analysis of the mouse transcriptome using the MPSS technique. This project is Victor Jongeneel got his Lic. Sc. From the University of Lausanne in not quite finished, as several of the selected tissue transcriptomes have 1974 and his PhD from the University of North Carolina at Chapel Hill , proven not be tractable to analysis by this technique. We have already USA (1980). He did his post doctoral training at the University of Cali- produced some interesting results from the dataset in its current state. fornia, San Francisco, USA between 1980 and 1983 and at the Swiss The data have also raised some important questions regarding the rela- Institute for Experimental Cancer Research (ISREC) between 1983 and tive information content and reliability of SAGE and MPSS data. We are 1985. He then became an Assistant Member and Associate Member of currently modeling the properties of the data generated by the two the Lausanne Branch of the Ludwig Institute for Cancer Research (LICR) types of experimental approaches using statistical methods, and veri- (1986–1996), and later Director of the Office of Information Techno- fying the models against experimental data, the aim being to establish logy, LICR worldwide (1998–2006), He is a founding Member and the reasonable criteria for the biological interpretation of such data. first Director of the Swiss Institute of Bioinformatics (SIB) (1998–2002), and is Associate Professor ad personam at the University of Lausanne Software development for genomics: C. Iseli has written a series of since 2002. He is associated with CIG since 2005 and is directing the software packages to perform sequence analysis tasks : high–through- Vital-IT Center since 2003. put alignment of cDNA to genome sequences (SIBsim4), fast mapping of large tag sequence collections to a reference genome or transcrip-

14 CIG 2005/2006 Group Publications Collaborations

Group leader Research articles signature sequencing (MPSS). C. Austin, Victor Jongeneel Genome Res 15 : 1007 National Institutes of Health (NIH), Bethesda, USA [email protected] Deutsch S, Lyle R, Dermitzakis Y. Chen, ET, Attar H, Subrahmanyan L, Armand F, Bucher P, Jonge- Cornell University Medical Center, New York, USA Assistant investigators Gehrig C, Parand L, Gagnebin neel CV, Farmer EE (2005) Christian Iseli M, Rougemont J, Jongeneel Rapid and selective surveillance M. Delorenzi, Brian Stevenson CV, Antonarakis SE (2005) of Arabidopsis thaliana genome NCCR Molecular Oncology and Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland Gene expression variation and annotations with Centrifuge. W. Hide, Bioinformatics expression quantitative trait Bioinformatics 21 : 2906 University of the Western Cape, Bellville, South Africa specialist mapping of human chromo- Dimitry Kuznetsov some 21 genes. Hum Mol Genet Grigoriadis A, Mackay A, F. Levy, 14 : 3741 Reis–Filho JS, Steele D, Iseli Ludwig Institute for Cancer Research (LICR), Lausanne, Switzerland Editorial assistant, C, Stevenson B, Jongeneel F. Naef, database curator Chen YT, Scanlan MJ, Ven- CV, Valgeirsson H, Fenwick K, EPFL (Ecole Polytechnique fédérale de Lausanne), Switzerland Monique Zahn–Zabal ditti CA, Chua R, Theiler G, Iravani M, Leao M, Simpson Stevenson BJ, Iseli C, Gure AS, Strausberg RL, Jat PJ, C. Notredame, Master student AO, Vasicek T, Strausberg RL, Ashworth A, Neville AM, CNRS, Marseille, France Ludivine Rielle Jongeneel CV, Old LJ, Simp- O’Hare MJ (2006) son AJ (2005) Establishment of the epithelial– A. Simpson, Ludwig Institute for Cancer Research (LICR), New York, USA Administrative Identification of cancer/testis–an- specific transcriptome of normal assistant tigen genes by massively parallel and malignant human breast A. Telenti, Jocelyne Muller signature sequencing. Proc Natl cells based on MPSS and array Centre Hospitalier Universitaire (CHUV) and University of Lausanne, Switzerland Acad Sci USA 102 : 7940 expression datA. Breast Cancer Res 8 : R56 Numerous collaborations through Vital-IT projects Chen YT, Venditti CA, Theiler G, Stevenson BJ, Iseli C, Gure Retelska D, Iseli C, Bucher P, AO, Jongeneel CV, Old LJ, Jongeneel CV, Naef F (2006) Simpson AJ (2005) Similarities and differences of Identification of CT46/HOR- polyadenylation signals in human MAD1, an immunogenic and fly. BMC Genomics 7 : 176 cancer/testis antigen encoding a putative meiosis–related protein. Chen YT, Iseli C, Venditti CA, Cancer Immun 7 : 5 Old LJ, Simpson AJ, Jonge- neel CV (2006) Jongeneel CV, Delorenzi M, Identification of a new cancer/ Iseli C, Zhou D, Haudenschild testis gene family, CT47, among CD, Khrebtukova I, Kuznetsov expressed multicopy genes on D, Stevenson BJ, Strausberg the human X chromosome. RL, Simpson AJ, Vasicek TJ Genes Chromosomes Cancer (2005) 45 : 392 An atlas of human gene expression from massively parallel

15 Research | The regulation of gene expression

Nouria Hernandez Mechanisms of transcription regulation Professor

With the sequencing of entire genomes from several organisms, we are damage. Thus, human Maf1 is a central regulator of pol III transcription faced with the challenge of understanding how individual genes are in human cells. Since pol III transcription is upregulated in malignant specifically expressed, and how such expression is regulated. A large cells, it is likely that either Maf1 itself or factors required for the activa- part of the regulation of gene expression occurs at the transcriptional tion of Maf1 are deregulated in cancer cells. level. We are interested in understanding fundamental mechanisms of transcription regulation. As a model system, we use the human small nuclear RNA (snRNA) genes. The U1 and U2 snRNA genes are transcribed by RNA polymerase (pol) II whereas the U6 snRNA gene is transcribed by pol III, yet all snRNA genes share very similar promoter structures and thus constitute a model system to study how RNA polymerase specificity is determined. Moreover, we can reconstitute ba- sal U6 transcription in vitro with well–defined factors; since the bas- al transcription machinery is the ultimate target of signal transduction pathways, this gives us a unique opportunity to study mechanisms of regulation. Lately we have concentrated on the characterization of the TFIIB–related factor 2 (Brf2), a key factor in the determination of pol III specificity, as well as on the identification of new factors that regulate pol III transcription.

TFIIB, Brf1, and Brf2 are part of a family of transcription factors that share very similar N–terminal zinc ribbon and core domains. Brf1 and Brf2 have in addition C–terminal extensions absent in TFIIB. TFIIB is essential for the recruitment of pol II to promoter sequences whereas Brf1 and Brf2 are essential for pol III transcription. We found that the C–terminal extension of Brf2, although at first sight unrelated to that of Brf1, has in fact a similar function, being essential for the assembly of a pol III preinitiaiton complex. This indicates that the C–terminal extensions in Brf1 and Brf2 are key to specific recruitment of pol III Nouria Hernandez performed her thesis research on mRNA splicing over pol II. with Dr. Walter Keller at the University of Heidelberg in Germany and received her PhD in 1983. She did her postdoctoral studies with Dr. To identify new players in the regulation of snRNA gene transcrip- Alan M. Weiner at Yale University in New Haven, Connecticut, USA, tion, we generated cell lines expressing a doubly tagged subunit of working on the 3’ end formation of the U1 small nuclear RNA. She the snRNA activating protein complex (SNAPc), a factor required for then joined Cold Spring Harbor Laboratory at Cold Spring Harbor, transcription of both pol II and pol III snRNA genes, and used this cell New York, USA, in 1986 as an Assistant Professor. She became a Cold line to purify SNAPc and associated factors. This led to the identifi- Spring Harbor Laboratory Professor in 1993 and joined the Howard cation of Yin Yang–1 (YY1) as a SNAPc – associated factor involved in Hughes Medical Institute first as an Associate Investigator in 1994, and the assembly of the U6 transcription initiation complex. Moreover, we as an Investigator in 1999. In 2005, she joined the faculty of the Uni- tested whether the human homolog of yeast Maf1 plays a role in pol versity of Lausanne as a Professor and as the Director of the Center for III transcription. Yeast Maf1 was recently identified as a factor required Integrative Genomics. for repression of pol III transcription after stress. Our results show that human Maf1 keeps pol III transcription in check in dividing cells and is required for repression of pol III transcription after stresses such as DNA

16 CIG 2005/2006 Group Publications Collaborations

GROUP LEADER Research articles Michels AA, Hernandez N C. Carles, Nouria Hernandez (2006) Life Sciences Division, CEA, Saclay, France [email protected] Kim Y–S, Kim J–M, Jung D–L, Does Pol I talk to Pol II? Coor- I . Grummt, Kang J–E, Lee S, Kim JS, Seol dination of RNA polymerases in German Cancer Research Center, Heidelberg, Germany TECHNICIAN W, Shin H–C, Kwon HS, Van ribosome biogenesis. Genes Dev Pascal Cousin Lint C, Hernandez N, Hur 20 : 1982–1985 Philippe L’Hôte M–W (2005) Artificial zinc–finger fusions Vieu E, Hernandez N (2006) MAITRE–ASSISTANT targeting Sp1 binding sites and Actin’s latest act : polymerizing Erwann Vieu** trans–activator–responsive ele- to facilitate transcription? Nat ment potently repress transcrip- Cell Biol. 8 : 650–651. POSTDOCTORAL FELLOWS Teldja Neige Azzouz tion and replication of HIV–1. J Michaël Boyer–Guittaut* Biol Chem 280 : 21545–21552 Annemieke Michels Erwann Vieu** Saxena A, Ma B, Schramm L, Hernandez N (2005) PhD STUDENTS Structure–function analysis of Agnès Déglon–Fischer* the human TFIIB–related factor II Jaime Humberto Reina protein reveals an essential role for the C–terminal domain in MASTER STUDENTS RNA polymerase III transcription. Claire Bertelli* Mol Cell Biol 25 : 9406–9418 Henrieta Hrobova Crausaz* Emran F, Florens L, Ma B, ADMINISTRATIVE Swanson SK, Washburn MP, ASSISTANT Nathalie Clerc Hernandez N (2006) A role for Yin Yang–1 (YY1) in *left the group the assembly of snRNA trans- **changed function cription complexes. Gene 377 : 96–108

Reina JH, Azzouz TN, Hernan- dez N (2006) Maf1, a new player in the regulation of human RNA polymerase III transcription. PLoS ONE 1:e134

17 Research | The regulation of gene expression

Winship Herr Regulation of cell proliferation Group Publications Professor

Two complete sets of instructions contained within the genomes we Group leader Research articles inherit from each of our parents are responsible for directing a sin- Winship Herr gle cell – the zygote – to become an adult human being. This process [email protected] Klejman MP, Zhao X, van results from controlled patterns of gene expression that are maintained Schaik FMA, Herr W, Timmers as well as changed during many rounds of cell division, differentiation, Technicians HThM (2005) and death. Control of gene transcription is fundamental to these pro- Philippe L’Hôte Mutational analysis of BTAF1–TBP cesses, with genetic and epigenetic defects in transcriptional regula- Fabienne Messerli interaction : BTAF1 can rescue tion often leading to human disease including cancer. DNA–binding defective TBP Postdoctoral fellows mutants. Nucleic Acids Res 33 : To investigate these processes, we study a key regulator of the human Pei–Jiun Chen 5426–5436 cell–proliferation cycle that was originally discovered in studies of her- Christina Hertel pes simplex virus (HSV) transcription – the HSV host–cell factor HCF–1. Virginie Horn Recent studies reveal that HCF–1 plays important roles in chromosome Joëlle Michaud function at distinct stages of the cell cycle. Sara Rodriguez–Jato Shweta Tyagi HCF–1 is unusual. It is an abundant, conserved, and chromatin–bound protein that undergoes proteolytic maturation resulting in stably asso- PhD students ciated amino– (HCF–1n) and carboxy– (HCF–1c) terminal subunits. Pro- Monica Albarca teolytic maturation to form heterodimeric HCF complexes has been Francesca Capotosti conserved between vertebrates and insects but the proteolytic mecha- Sophie Guernier nisms involved differ. We hypothesize that the mechanisms of HCF– protein maturation have evolved more than once. MASTER STUDENT Coralie Carrascosa In human cells, the HCF–1n and HCF–1c subunits play roles in two separate cell–cycle phases : the G1 and M phases, respectively. Con- Administrative sistent with pivotal roles in these processes, the HCF–1n subunit pro- assistant motes G1–phase progression by associating with regulators of G1– Nathalie Clerc phase transcription and recruiting trithorax–related histone H3 lysine Winship Herr received his PhD from Harvard University in 1982 for 4 methyltransferases of the mixed–lineage leukemia family to promo- studies on recombinant retroviruses in leukemogenic mice with Wal- ters to effect histone modification and transcriptional activation. In ter Gilbert. After postdoctoral studies with Frederick Sanger in Cam- contrast, during mitosis, the HCF–1c subunit controls chromosome bridge, UK, and Joe Sambrook at Cold Spring Harbor Laboratory, USA, dynamics, and histone phosphorylation and methylation, as well as he joined the Cold Spring Harbor Laboratory faculty in 1984. There associates with mitotic structures. We hypothesize that the two differ- he served as assistant director of the Laboratory from 1994–2002 and ent subunits, via regulated association, influence each other’s activity from 1998–2004 was the founding dean of the Watson School of Bio- and help coordinate the M/G1 phase of the cell cycle. logical Sciences, a doctoral degree–granting school. He arrived at the CIG in September 2004. Our current interests continue to focus on understanding how HCF–1 regulates cell proliferation – especially as it pertains to cancer – and cell differentiation.

18 CIG 2005/2006 Collaborations

A. Busturia, Universidad Autonoma de Madrid, Madrid, Spain M. Hengartner, University of Zurich, Zurich, Switzerland J. Hsieh, Washington University of California, St. Louis, USA J. Tamkun, University of California, Santa Cruz, USA

19 Research | The regulation of gene expression

Christian Fankhauser Light–regulated development in plants Group Publications Associate professor

Growth and development are influenced by both genetic and envi- GROUP LEADER Research articles ronmental factors. The effect of the environment is particularly appa- Christian Fankhauser rent in the sessile plants. Being photoautotrophic, plants are exquisitely [email protected] Hiltbrunner A, Viczián A, sensitive to changing light conditions. Molecular genetic studies in the Bury E, Tscheuschler A, Kir- model plant Arabidopsis thaliana have identified 3 photoreceptor fami- TECHNICIANS cher S, Tóth R, Honsberger A, lies that are present in all higher plants : the blue light sensing cryp- Laure Allenbach Nagy F, Fankhauser C, Schäfer tochromes and phototropins, and the phytochromes that maximally Martine Trevisan E (2005) absorb red and far–red light (cry1–cry3, phot1, phot2, phyA–phyE in Nuclear accumulation of the Arabidopsis). Photon capture by these photoreceptors induces a suite POSTDOCTORAL FELLOWS phytochrome A photoreceptor of developmental responses including seed germination, seedling de– Paula Duek Roggli* requires FHY1. Curr Biol 15 : etiolation, regulation of tropic growth, shade avoidance and the con- Thierry Genoud 2125–2130 trol of flowering time. Recent progress in deciphering phytochrome Chitose Kami signaling has revealed : 1) in response to light the phytochromes enter Séverine Lorrain Lariguet P, Schepens I, Hodg- the nucleus where they can directly interact with several bHLH class Isabelle Schepens son D, Pedmale UV, Trevisan transcription factors (referred to as PIFs) suggesting that the phyto- M, Kami C, de Carbonnel M, chromes may directly modulate light–regulated gene expression, 2) the PhD STUDENTS Alonso JM, Ecker JR, Liscum E, importance of light–regulated proteolysis involving the evolutionary Matthieu De Carbonnel Fankhauser C (2006) conserved E3 ligase COP1 (COnstitutively Photomorphogenic 1); se- Dimitry Debrieux Phytochrome Kinase Substrate 1 veral phytochrome signaling components including phyA and members Vincent Fiechter is a phototropin 1 binding pro- of the PIF family are subjected to this regulation, 3) cytoplasmic events Patricia Hornitschek tein required for phototropism. in phytochrome signaling are still very poorly understood. Proc Nat Acad Sci USA 103 : MASTER STUDENT 10134–10139 Our studies are mainly but not exclusively centered on phyA. At the Fabian Schweizer physiological level we primarily analyze two responses : light regula- Review articles tion of tropic growth and the shade avoidance response. Recent stu- ADMINISTRATIVE dies have shown that these two modes of adaptation are particularly ASSISTANT Duek PD, Fankhauser C (2005) important to determine the success of plants grown in dense vegeta- Nathalie Clerc BHLH class transcription factors tion. At the molecular level we study phyA signaling in the cytoplasm take center stage in phytochro- Christian Fankhauser carried out his thesis at the Swiss Institute for and the nucleus. PKS1 (Phytochrome Kinase Substrate 1) is the star- *left the group me signalling. Trends Plant Sci Experimental Cancer Research (ISREC) in the laboratory of Dr. Viesturs ting point for our exploration of cytoplasmic events. PKS1 is a cytoplas- 10 : 51–54 Simanis and received his PhD from the University of Lausanne in 1994. mically–localized phy–signaling component member of a gene family He did his postdoctoral training with Dr. Marty Yanofsky at University in Arabidopsis (PKS1–PKS4). HFR1 (long Hypocotyl in FR light 1) is a Lorrain S, Genoud T, Fankhau- of California, San Diego, USA, and then with Dr. Joanne Chory at The nuclear phyA–signaling component related to the PIFs. The abundance ser C (2006) Salk Institute for Biological Studies in San Diego. He then moved to of HFR1 is regulated by COP1 and phosphorylation. Studying the role Let there be light in the nucleus! the University of Geneva in 2000 as a Swiss National Science Foun- of phosphorylation and light–regulated proteolysis is a central element Curr Opin Plant Biol 9 : 509–514 dation Assistant Professor at the Department of Molecular Biology. of our research. Finally we are particularly interested in identifying the He joined the Center for Integrative Genomics in January 2005 as an target genes of members of the PIF family of bHLH class transcription associate Professor. factors during light–controlled gene expression.

20 CIG 2005/2006 Collaborations

Book chapters Y. Barral, Swiss Federal Institute of Technology Zurich (ETHZ), Switzerland Lariguet P, Fankhauser C J. Casal, (2005) University of Buenos Aires, Argentina The effect of light and gravity on hypocotyl growth orientation. M. Geisler and E Martinoia, In : Light Sensing in Plants; Wada University of Zurich, Switzerland M and Shimazaki K eds; Springer U. Genick, Verlag, Tokyo University of Brandeis, USA Fankhauser C, Bowler C R. Hedrich, (2006) University of Würzburg, Germany Biochemical and molecular ana- E. Liscum, lysis of signaling components. In : University of Missouri, Columbia, USA Photomorphogenesis in Plants; Schaefer E and Nagy F eds; J. Maloof, Kluwer, Dortrecht University of California, Davis, USA A. Murphy, Popularization University of Purdue, USA Fankhauser C, Lorrain S E. Schaefer, (2006) University of Freiburg, Germany Quand les plantes sortent de C. de Virgilio, l’ombre. Pour la Science 349 : University of Geneva, Switzerland 68–73 G. Whitelam, University of Leicester, UK

21 R esearch | The genomics of complex functions

Mehdi Tafti Genetics of sleep and the sleep EEG Group Publications Associate professor

Based on available literature there is no doubt that many aspects of GROUP LEADER Research articles sleep are under a genetic control in both humans and animal models. Mehdi Tafti These include not only the amount and the distribution of sleep but [email protected] Maret S, Franken P, Dau- also very specific electroencephalographic (EEG) features of sleep and villiers Y, Ghyselinck NB, wakefulness. By using the inbred mouse as a genetic tool, we have TECHNICIANS Chambon P, Tafti M (2005) been able to demonstrate that sleep as a quantitative trait is amenable Brice Petit Retinoic acid signaling affects to quantitative trait loci analysis (QTL). Although many genes with small Corinne Pfister cortical synchrony during sleep. effects might affect the amount and the distribution of sleep, some Science 310 : 111–113 aspects such as the daily amount of paradoxical sleep may be under POSTDOCTORAL FELLOWS a major gene control. We have localized such a gene on the mouse Laure Gurcel** Baumann CR, Kilic E, Petit B, chromosome 1 and are currently fine mapping the region to ultimately Anne Vassali Werth E, Hermann DM, Tafti identify the responsible gene. We have been the first to report that a M, Bassetti CL (2006) single gene may dramatically affect the quantitative sleep EEG. An EEG PhD STUDENTS Sleep EEG changes after middle variant specific to paradoxical sleep (slow theta frequency) has been Stéphane Dorsaz cerebral artery infarcts in mice : identified as the most heritable phenotype in inbred mice and subse- Laure Gurcel** different effects of striatal quent mapping and functional studies identified Acads (acyl Coenzyme Subah Hasan and cortical lesions. Sleep 29 : A dehydrogenase for short chain fatty acids) as the underlying gene. Stéphanie Maret 1339–1344 More recently, we have shown that the slow wave activity during sleep Danielle Mersch is also affected by a single gene (Rarb) involved in the vitamin A signa- Julie Vienne ling pathway. We are now concentrating our research efforts on the Huang YS, Tafti M, Guillemi- nault C (2006) genetic dissection of sleep need. Sleep need is homeostatically regula- MASTER STUDENTS ted (loss of sleep leads to compensatory processes, which are responsi- Valérie Calpini* Daytime sleepiness with and ble for deeper recovery sleep). A gene for sleep need has been mapped Sébastien Del Rizzo without cataplexy in Chinese– on the mouse chromosome 13. Fine mapping studies in the identified Anne–Catherine Robyr* Taiwanese patients. Sleep Med region are ongoing. We use also gene expression profiling after sleep Salma Tawffik* 7 : 454–457 deprivation to investigate the molecular correlates of prolonged wakefulness. Finally, we are interested in sleep and circadian rhythms and ADMINISTRATIVE Rissling I, Frauscher B, Kro- their molecular basis in social species such as ants. ASSISTANT nenberg F, Tafti M, Stiasny– Mehdi Tafti received his PhD from the University of Montpellier (France) Annick Crevoisier Kolster K, Robyr AC, Korner Y, in 1991 after completing his doctoral thesis on sleep regulation in Genetics of sleep disorders Oertel WH, Poewe W, Hogl B, human narcolepsy. He performed a postdoctoral fellowship with Dr. *left the group Moller JC (2006) Mignot and Dr. Dement and was a Research Associate at the Depart- Many sleep disorders run in families but their genetic bases are poor- **changed function Daytime sleepiness and the ment of Psychiatry and Biological Sciences at Stanford University, USA. ly understood. Our laboratory is specialized in the genetics of narco- COMT val158met polymorphism In 1995 he moved to the Department of Psychiatry at the University lepsy and sleepwalking. We perform family– and population–based in patients with Parkinson di- of Geneva where he established the first laboratory dedicated to the studies using linkage, candidate gene, and genome–wide associations. sease. Sleep 29 : 108–111 molecular genetics of sleep and sleep disorders. He joined the Center We have also initiated a new Center for Investigation and Research on for Integrative Genomics in September 2004. Since November 2006, Sleep (CIRS) in collaboration with the Medical Department of the CHUV he is co–directing the Center for Investigation and Research in Sleep (Centre Hospitalier Universitaire Vaudois), where we plan to conduct (CIG–CHUV (Centre Hospitalier Universitaire Vaudois)). sleep research in normal subjects and patients with sleep disorders. We have localized the first familial susceptibility gene for narcolepsy and have reported the first genetic evidence in sleepwalking. Future plans include genetics of normal sleep in twins and families.

22 CIG 2005/2006 Collaborations

Review articles B. Bettler, University of Basel, Switzerland Maret S, Tafti M (2005) Y. Dauvilliers, Genetics of narcolepsy and other Centre Hospitalier Universitaire (CHU), Montpellier, France major sleep disorders. Swiss Med Wkly 135 : 662–665 L. Keller, University of Lausanne, Switzerland Tafti M, Maret S, Dauvilliers M. Mühlethaler, Y (2005) University of Geneva, Switzerland Genes for normal sleep and sleep disorders. Ann Med 37 : U. Schibler, 580–589 University of Geneva, Switzerland

Dauvilliers Y, Maret S, Tafti M (2005) Genetics of normal and patholo- gical sleep in humans. Sleep Med Rev 9 : 91–100

Dauvilliers Y, Tafti M (2006) Molecular genetics and treatment of narcolepsy. Ann Med 38 : 252–262

23 Research | The genomics of complex functions

Paul Franken Genetics and Energetics of sleep homeo- Group Publications Maître d’enseignement et de recherche stasis and circadian rythms

In the study of sleep two main regulatory processes have to be con- Group leader Research articles sidered : a homeostatic process that is activated by and counters the Paul Franken effects of sleep loss and a circadian process that determines the time– [email protected] Xie X, Dumas T, Tang L, Bren- of–day sleep preferably occurs. The fine–tuned interaction between nan T, Reeder T, Thomas W, the two permits us to stay awake and alert throughout the day and to Technician Klein RD, Flores J, O’Hara BF, remain asleep at night. To gain inside into the molecular correlates of Yann Emmenegger Heller HC, Franken P (2005) the homeostatic process and its interaction with the circadian process Lack of the alanine–serine–cys- we apply both forward and reverse genetic approaches in the mouse. Postdoctoral fellow teine transporter 1 causes Thomas Curie tremors, seizures, and early Using Quantitative Trait Loci (QTL) analysis as a forward genetics tool postnatal death in mice. Brain we found several genomic regions affecting sleep and EEG traits indi- Res 1052 : 212–221 cating the presence of major genes. Especially EEG traits were found to be under strong genetic control. Thus far, we were successful in iden- Maret S, Franken P, Dau- tifying the genes modifying two such traits thereby implicating novel villiers Y, Ghyselinck NB, signaling pathways involved in rhythmic brain activity. Currently, we Chambon P, Tafti M (2005) focus on fine mapping the dps1 QTL that alters the highly predictive Retinoic acid signaling affects relationship between time–spent–awake and EEG delta power hoping cortical synchrony during sleep. to identify the molecular mechanisms of sleep homeostasis. Science 310 : 111–113

Although the circadian and homeostatic processes are thought to Franken P, Dudley D, Estill operate independently, we found that the genes known to set cir- S–J, Barakat M, Thomason cadian time are also involved in the homeostatic regulation of sleep. R, O’Hara BF, McKnight SL Thus, in mice that lack one or more of the core clock components (e.g. (2006) clock, bmal1, npas2, cry1 and cry2) sleep homeostasis is altered. We The transcription factor NPAS2 also showed that the expression of the clock genes per1 and per2 in affects the regulation and EEG of the forebrain is tightly linked to the prior sleep–wake history. Thus at non–REM sleep : genotype and a cellular level the same molecular circuitry seems to be implicated sex interactions. Proc Natl Acad in both circadian rhythms and sleep homeostasis. We investigate the Sci USA 103 : 7118–7123 Paul Franken received his PhD from the University of Groningen, Ne- mechanisms that link clock gene expression to the time–spent–awake. therlands, in 1993 for his work on sleep homeostasis and thermoregu- The observation that the transcriptional activity of CLOCK and NPAS2 Franken P, Gip P, Hagiwara G, lation at the University of Zurich under the direction of Alexander A. depends on and affects intracellular energy charge is an exciting first Ruby NF, Heller HC (2006) Borbély. He was a postdoctoral fellow with H. Craig Heller at Stanford clue we are currently pursuing by using redox–sensitive GFP probes and Glycogen content in the cerebral University, USA, where he studied the cellular mechanisms underlying developing in vivo imaging techniques. cortex increases with sleep loss circadian clock resetting. In 1996 he joined Mehdi Tafti at the Univer- in C57BL/6J mice. Neuroscie Lett sity of Geneva where he used QTL analysis to map sleep and EEG traits 402 : 176–179 in mice. He then moved back to Stanford in 2000 as a senior research scientist to establish an independent lab. At Stanford he continued to Flores AE, Flores JE, Desh- work on the genetics of sleep homeostasis and further focused on the pande H, Picazo JA, Xie S, molecular interactions between circadian rhythms, sleep homeostasis, Franken P, Heller HC, Grahn and brain metabolism. He joined the Center for Integrative Genomics DA, O’Hara BF (2006) in 2005. Pattern recognition of sleep in rodents using piezoelectric

24 CIG 2005/2006 Collaborations

signals generated by gross body R. Chrast, movements IEEE Trans Biomed University of Lausanne, Switzerland Eng (in press) C. Grundschober and C. Lopez, Roche, Basel, Switzerland Book chapter H . Craig Heller and P. Bourgin, Dijk DJ, Franken P (2005) Stanford University, USA Interaction of sleep homeostasis S. McKnight, and circadian rhythmicity – de- UT Southwestern Medical Center, Dallas, USA pendent or independent systems. In : Principles and Practice B. O’Hara, of Sleep Medicine 4th Edition; University of Kentucky, Lexington, USA Kryger MH, Roth Th and Dement M. Tafti, W Eds; W.B. Saunders Company, University of Lausanne, Switzerland Philadelphia

25 Research | The genomics of complex functions

Walter Wahli Peroxisome Proliferator-Activated Receptors (PPARs) as regulators of metabolic Professor and tissue repair processes

The three Peroxisome Proliferator–Activated Receptors (PPARs) are lipolysis, and glycerol export, but also, more surprisingly, networks of nuclear receptors that act as lipid sensors to modulate gene expres- genes involved in IR/IGF–1 signaling, cellular integrity, detoxification, sion. They are implicated in major metabolic and inflammatory regu- and inflammation/immunity. These results unveil novel roles of PPAR- lations with far–reaching medical consequences, and in important gamma in the adipose tissue and underscore the multifaceted action mechanisms controlling cellular fate. PPARs exhibit a broad but iso- of this receptor in the fine–tuned functioning of this major tissue in the type–specific tissue expression pattern, which can account for the vari- healthy and diseased organism. ety of cellular functions they regulate. This diversity of functions is also reflected by the broad range of ligands that can be accommodated within their ligand binding pocket. These ligands are naturally occur- ring or diet–derived lipids, which include diverse fatty acids, leukot- rienes and prostaglandins. Recently, we have analyzed the functions of two of the three PPAR isotypes, PPARbeta in wound–healing and PPARgamma in adipogenesis.

Healing of cutaneous wounds proceeds via a pattern of events including inflammation, re–epithelialization, and tissue remodeling. We have shown that the inflammation that immediately follows injury increases the expression of PPARbeta (also called PPARdelta) and triggers the production of endogenous PPARbeta ligands. PPARbeta then activates a major cellular survival pathway, which protects keratinocytes from death at the site of injury. We have also demonstrated that transforming growth factor beta (TGFbeta1) down regulates the action of inflammation–induced PPARbeta, thereby participating in the coordination of re–epithelialization. This latter event depends on directional sensing and migration of keratinocytes. We found that the activation of PPARbeta amplifies intracellular signals required for cellular directional sensing, cell polarization and pseudopodia extension. These processes are delayed and reduced in PPARbeta–null keratino- After receiving his PhD in Bern, Walter Wahli carried out his postdoc- cytes. Consistently, early wound biopsies of PPARbeta–null mice reveal toral education with Dr. Igor Dawid at the Department of Embryology, uncoordinated migratory fronts at the wound edge demonstrating a Carnegie Institution of Washington in Baltimore, USA. He then was at defect in directional sensing. Together, these observations reveal the the Department of Biochemistry of the National Cancer Institute, NIH, molecular mechanisms by which PPARbeta and its ligands contribute in Bethesda, USA, as visiting fellow and visiting associate. He moved to to wound closure. Lausanne 1980, and is the Founding Director of the Center for Integra- tive Genomics (2002–2005). PPARgamma is involved in adipocyte differentiation and insulin sensitivity. Synthetic ligands, the thiazolidinediones (TZD), are used as insulin sensitizers in the treatment of type 2 diabetes. PPARgamma serves as an essential regulator of adipocyte differentiation and lipid storage, and is required for maintenance and survival of mature adult adipocytes. Deregulations of its functions are thought to account for diseases such as obesity and diabetes. We found recently that deletion of one PPAR- gamma allele not only affects lipid synthesis, pentose phosphate shunt,

26 CIG 2005/2006 Group Publications

GROUP LEADER MASTER STUDENTS Research articles Sellers JA, Hou L, Schoenberg Genolet R, Kersten S, Brais- FRET calculation which can ac- Walter Wahli David Barras* DR, Batistuzzo de Medeiros sant O, Mandard S, Tan NS, commodate variations in spectral [email protected] David Brawand* Gremlich S, Nolan C, Roduit SR, Wahli W, Shelness GS Bucher P, Desvergne B, Mi- bleed–throughs. Microsc Res Henrieta Hrobova Crausaz* R, Burcelin R, Peyot ML, (2005) chalik L, Wahli W (2005) Techn 68 : 51–58 MAITRE D’ENSEIGNEMENT Matteo Ricci Delghingaro–Augusto V, Des- Microsomal triglyceride transfer Promoter rearrangements cause ET DE RECHERCHE vergne B, Michalik L, Prentki protein promotes the secretion species–specific hepatic regula- Zandbergen F, Mandard S, Liliane Michalik APPRENTICES M, Wahli W (2005) of Xenopus laevis Vitellogenin tion of the glyoxylate reductase/ Escher P, Tan NS, Patsouris Vanessa Hassler Pancreatic islet adaptation to fas- A1. J Biol Chem 280 : 13902– hydroxypyruvate reductase gene D, Jatkoe T, Rojas–Caro S, ANIMAL KEEPER Nataskha Pernet ting is dependent on PPARalpha 13905 by the peroxisome proliferator– Madore S, Wahli W, Tafuri S, Marianne Wertenberg Angélique Vaucher transcriptional up–regulation of activated receptor alphA. J Biol Müller M, Kersten S (2005) fatty acid oxidation. Endocrino- Tan NS, Michalik L, Desvergne Chem 280 : 24143–24152 The G0/G1 switch gene 2 is a TECHNICIANS ADMINISTRATIVE logy 146 : 375–382 B, Wahli W (2005) novel PPAR target gene. Biochem Berendina Bordier ASSISTANT Genetic– or TGF–beta 1–induced Metzger D, Imai T, Jiang M, J 392 : 313–324 Christiane Freymond Marlène Petit Skrtic S, Carlsson L, Ljung- changes in epidermal PPARbeta/ Takukawa R, Desvergne B, Sylvia Moreno Joanna Schwab* berg A, Lindén D, Michalik L, delta expression dictate wound Wahli W, Chambon P (2005) Yang ZZ, Tschopp O, Di–Poï N, Norman Moullan Wahli W, Oscarsson J (2005) repair kinetics. J Biol Chem 280 : Functional role of RXRs and Bruder E, Baudry A, Duem- Corinne Tallichet Blanc *left the group Decreased expression of PPARal- 18163–18170 PPARgamma in mature adipocy- mler B, Wahli W, Hemmings pha and liver fatty acid binding tes. Prostaglandins Leukot Essent BA (2005) MAITRES–ASSISTANTS **changed function protein after partial hepatectomy Feige JN, Gelman L, Tudor Fatty Acids 73 : 51–58 Dosage–dependent effects Laurent Gelman* of rats and mice. Liver Int 25 : C, Engelborghs Y, Wahli W, of Akt1/PKBalpha and Akt3/ Nicolas Rotman** 33–40 Desvergne B (2005) Michalik L, Feige JN, Gelman PKBgamma on thymus, skin, car- Fluorescence imaging reveals the L, Pedrazzini T, Keller H, Des- diovascular and nervous system POSTDOCTORAL FELLOWS Planavila A, Rodriguez–Calvo nuclear behavior of PPAR/RXR vergne B, Wahli W (2005) development in mice. Mol Cell Anen Delgado* R, Jové M, Michalik L, Wahli heterodimers in the absence and Selective expression of a domi- Biol 25 : 10407–10418 Radina Kostadinova W, Laguna JC, Vàzquez–Car- presence of ligand. J Biol Chem nant negative form of PPAR in Alexandra Krauskopf rera M (2005) 280 : 17880–17890 keratinocytes leads to impaired Debril MB, Dubuquoy L, Feige Alexandra Montagner Peroxisome proliferator–ac- epidermal healing. Mol Endocri- J, Wahli W, Desvergne B, Nicolas Rotman** tivated receptor beta/delta Rousseaux C, Lefebvre B, nol 19 : 2335–2348 Auwerx J, Gelman L (2005) Zofia Terreau–Haftek activation inhibits hypertrophy Dubuquoy L, Lefebvre P, Ro- Scaffold attachment factor B1 in neonatal rat cardiomyocytes. mano O, Auwerx J, Metzger Letavernier E, Perez J, Joye E, directly interacts with nuclear PhD STUDENTS Cardiovasc Res 65 : 832–841 D, Wahli W, Desvergne B, Bellocq A, Fouqueray B, Hay- receptors in living cells and Silvia Anghel Naccari GC, Chavatte P, Farce mann JP, Heudes D, Wahli W, represses transcriptional activity. David Brawand* Di–PoïN N, g CY, Tan NS, Yang A, Bulois P, Cortot A, Colom- Desvergne B, Baud L (2005) J Mol Endocrinol 35 : 503–517 Nathalie Constantin Z, Hemmings BA, Desvergne bel JF, Desreumaux P (2005) Peroxisome Proliferator–Activa- Ilhem El Kochairi B, Michalik L, Wahli W (2005) Intestinal antIInflammatory effect ted Receptor beta/delta Exerts a Di–Poï N, Desvergne B, Mi- Guillaume Icre* Epithelium–mesenchyme of 5–aminosalicylic acid is de- Strong Protection from Ischemic chalik L, Wahli W (2005) José Iglesias interactions control the activity pendent on peroxisome prolife- Acute Renal Failure. J Am Soc Transcriptional repression of Virginie Jeronimo of PPARbeta/delta during hair rator–activated receptor gammA. Nephrol 16 : 2395–2402 peroxisome proliferator–activa- Caroline Lathion* follicle development. Mol Cell J Exp Med 201 : 1205–1215 ted receptor beta/delta in murine Nicolas Leuenberger Biol 25 : 1696–1712 Feige JN, Sage D, Wahli W, keratinocytes by CCAAT/enhan- Desvergne B, Gelman L (2005) cer–binding proteins. J Biol Chem PixFRET, an ImageJ plug–in for 280 : 38700–38710

continued on next page >>> 27 Publications (continued)

The Eumorphia Consortium. A li FY, Egan K, Fitzgerald Varnat F, Bordier–ten–Heg- Wang D, Wang H, Guo Y, Review articles Reddy JK, Spiegelman BM, Authors from the Center for GA, Desvergne B, Wahli W, geler B, Grisel P, Boucard N, Ning W, Katkuri S, Wahli W, Staels B, Wahli W (2006) Integrative Genomics, Univer- Bishop–Bailey D, Warner TD, Corthésy–Theulaz I, Wahli W, Desvergne B, Dey SK, DuBois Gelman L, Michalik L, Desver- International Union of Phar- sity of Lausanne : Wahli W, Mitchell JA (2006) Desvergne B (2006) RN (2006) gne B, Wahli W (2005) macology. LXI. Peroxisome Delgado MB, Desvergne B, Role of prostacyclin receptor PPARbeta/delta regulates paneth Crosstalk between peroxisome Kinase signaling cascades that Proliferator–Activated Receptors. Michalik L, Bedu E (2005) versus PPAR–beta with trepros- cell differentiation via control- proliferator–activated receptor modulate peroxisome prolife- Pharmacol Rev 58 : 726–741 EMPReSS : standardised pheno- tinil sodium on lung fibroblast ling the hedgehog signalling delta and VEGF stimulates cancer rator–activated receptors. Curr type screens for functional anno- proliferation. Am J Respir Cell pathway. Gastroenterology 131 : progression. Proc Natl Acad Sci U Opin Cell Biol 17 : 216–222 Feige JN, Gelman L, Micha- tation of the mouse genome. Nat Mol Biol 34 : 242–246 538–553 S A 103 : 19069–19074 lik L, Desvergne B, Wahli W Genet 37 : 1155 T an NS, Michalik L, Desvergne (2006) Nadra K, Anghel SI, Joye E, Schuler M, Ali F, Chambon C, B, Wahli W (2005) From molecular action to Canaple L, Rambaud J, Tan NS, Basu–Modak S, Trono Duteil D, Bornet JM, Tardivel Multiple expression control physiological outputs : Peroxi- Dkhissi–Benyahya O, Rayet B, D, Wahli W, Desvergne B A, Desvergne B, Wahli W, mechanisms of peroxisome some proliferator–activated Tan NS, Michalik L, Delaunay (2006) Chambon P, Metzger D (2006) proliferator–activated receptors receptors are nuclear receptors F, Wahli W, Laudet V (2006) Differentiation of trophoblast PGC1alpha expression is and their target genes. J Steroid at the crossroads of key cellular Reciprocal regulation of brain giant cells and their metabolic controlled in skeletal muscles by Biochem Mol Biol 93 : 99–105 functions. Prog Lipid Res 45 : and muscle Arnt–like protein 1 functions are dependent on pe- PPARbeta, whose ablation results 120–159 and peroxisome proliferator–ac- roxisome proliferator–activated in fiber type switching, obesity Kostadinova R, Wahli W, tivated receptor alpha defines a receptor beta/delta. Mol Cell Biol and type 2 diabetes. Cell Metab Michalik L (2005) Icre G, Wahli W, Michalik L novel positive feedback loop in 26 : 3266–3281 4 : 407–414 PPARs in disease : control mecha- (2006) the rodent liver circadian clock. nisms of inflammation. Curr Med Functions of the Peroxisome Mol Endocrinol 20 : 1715–1727 Gelman L, Feige JN, Tudor Avallone R, Demers A, Rodri- Chem 12 : 2995–3009 Proliferator–Activated Receptor C, Engelborghs Y, Wahli W, gue–Way A, Bujold K, Harb D, (PPAR) alpha and beta in Skin Mandard S, Zandbergen Desvergne B (2006) Anghel S, Wahli W, Marleau Homeostasis, Epithelial Repair, Mutch DM, Wahli W, William- F, van Straten E, Wahli W, Integrating nuclear receptor mo- S, Ong H, Tremblay A (2006) and Morphogenesis. J Invest son G (2005) Kuipers F, Müller M, Kersten bility in models of gene regula- A growth hormone–releasing Dermatol 126 Suppl : 30–5 Nutrigenomics and nutrigene- S (2006) tion. Nucl Recept Signal 4 : e010 peptide that binds Scavenger tics : the emerging faces of nutri- The fasting–induced adipose receptor CD36 and Ghrelin tion. FASEB J 19 : 1602–1616 Lathion C, Michalik L, Wahli factor/angiopoietin–like protein Knauf C, Rieusset J, Foretz M, receptor up–regulates ade- W (2006) 4 is physically associated with Cani PD, Uldry M, Hosokawa nosine Triphosphate–binding Physiological ligands of PPARs in Bedu E, Wahli W, Desvergne lipoproteins and governs plasma M, Martinez E, Bringart M, cassette sterol transporters and inflammation and lipid homeos- B (2005) lipid levels and adiposity. J Biol Waget A, Kersten S, Desver- cholesterol efflux in macro- tasis. Future Lipidology Peroxisome proliferator–acti- Chem 281 : 934–944 gne B, Gremlich S, Wahli W, phages through a peroxisome 1 : 191–201 vated receptor beta/delta as a Seydoux J, Delzenne NM, proliferators–aactivated receptor therapeutic target for metabolic Thorens B, Burcelin R (2006) gamma–dependent pathway. Desvergne B, Michalik L, Wa- diseases. Expert Opin Ther Peroxisome proliferators–acti- Mol Endocrinol 20 : 3165–3178 hli W (2006) Targets 9 : 861–873 vated receptor–alpha–null mice Transcriptional regulation of have increased white adipose metabolism. Physiol Rev 86 : Michalik L, Auwerx J, Berger tissue glucose utilization, GLUT4, 465–514 and fat mass : Role in liver and JP, Chatterjee VK, Glass CK, brain. Endocrinology 147 : Gonzalez FJ, Grimaldi PA, 4067–4078 Kadowaki T, Lazar MA, O’ra- hilly S, Palmer CN, Plutzky J, 28 CIG 2005/2006 Collaborations

Michalik L, Wahli W (2006) K. Buttler, Involvement of PPAR nuclear Universitätsklinik Göttingen, Germany receptors in tissue injury and D. Dombrowicz, wound repair. J Clin Invest Institut Pasteur, Lille, France 116 : 598–606 D. Duboule, Rotman N, Michalik L, Desver- University of Geneva, Switzerland gne B, Wahli W (2006) E. Hafen, PPARs in fetal and early postna- University of Zurich, Switzerland tal development. Advances in Developmental Biology 16 P. Herrera, University of Geneva, Switzerland Book chapters S. Nef, University of Geneva, Switzerland Varnat F, Michalik L, Desver- gne B, Wahli W (2006) U. Schibler, PPARs : lipid sensors that regu- University of Geneva, Switzerland late cell differentiation processes. M. Swartz, In : Nutritional Genomics : Impact EPFL (Ecole Polytechnique Fédérale de Lausanne), Switzerland on Health and Disease; Brige- lius–Flohé R and Joost HG eds; B. Thorens, Wiley–VCH Verlag GmbH & Co. University of Lausanne, Switzerland KGaA, Weinheim S. Werner, Swiss Federal Institute of Technology Zurich (ETHZ), Switzerland Michalik L, Wahli W (2006) PPARs and colon cancers : A Bioresearch and Partners, curse or a cure? In : Recent Monthey, Switzerland Advances in Gastrointestinal Carcinogenesis; Bamba H and Institut de recherche Pierre Fabre Dermo–cosmétique, Ota S eds; Transworld Research Toulouse, France Network, India

29 Research | The genomics of complex functions

Béatrice Desvergne PPAR beta and fine tunig Associate professor of cell fate decision

As they mediate intracellular hormone action, nuclear receptors play a in vivo to prevent backleakage of the glomerular filtrate during ischemic crucial multi–faceted role in coordinating growth during development, acute renal failure. Based on these studies, PPARbeta ligands seem to and homeostasis at adult stage. Among them, the peroxisome–prolif- exert their protection in ischemic acute renal failure by both activating erator activated receptors (PPARs) act as fatty acids sensors, respond- the antiapoptotic Akt signaling pathway and increasing epithelial cell ing to dietary as well as to endogenous challenges. Accordingly, they spreading. These results point to PPARbeta as a remarkable target for have an integrative role in controlling the expression of genes regulat- preconditioning strategies. ing the storage, mobilisation, and / or utilisation of lipids. Using various molecular, cellular, and animal approaches, our studies are aimed at understanding how PPARs are integrated in the main pathways that shape the organism during development on the one hand and main- tain systemic homeostasis on the other hand.

During development we first demonstrated the crucial role of PPAR- beta in the placenta. Indeed, PPARbeta is required for a proper differentiation of the trophoblast giant cell, via i) activation of the PI3K pathway II) inhibition of Id2 (inhibitor of differentiation 2) gene expression III) activation of Imfa1 gene expression. In the intestine, PPARbeta also promotes Paneth cell differentiation. However, the exploration of the corresponding molecular signalling lead us to uncover the inhibitory role of Indian Hedgehog on Paneth cell terminal differentiation. Our works demonstrate that Ihh is expressed at high levels in the Paneth cells of the adult intestine and that moderation via PPARbeta ensures the final maturation of Paneth cell precursors.

Because of our observations concerning the crucial role of PPARbeta in tissue repair seen in the skin (in collaboration with W. Wahli and L. Michalik), we explored the possible role of PPARbeta in various tissue injuries, with a dual aim : identifying the molecular mechanism con- Béatrice Desvergne was trained as a MD. She initially specialized in trolled by PPARbeta in these contexts, and identifying possible clinical anesthesiology and reanimation, practiced medicine for a few years, applications of PPARbeta activators. The models we have been using but decided to move for fundamental research. After a further train- reflect quite common clinical situations : gut epithelial damages pro- ing in biology, she carried out a post–doctoral stay from 1988 to 1992 voked by gamma–irradiation, acute ischemic renal failure, and middle at the National Institutes of Health in Bethesda, USA, first as visiting cerebral artery occlusion. The most advanced work concerns the pro- fellow and then visiting associate in the National Institute of Diabe- tective role of PPARbeta upon aute ischemic renal failure. We indeed tes and Digestive and Kidney Diseases. In 1992, she was appointed as have shown that PPARbeta+/- and PPARbeta-/- mutant mice exhibit assistant professor at the Institute of Animal Biology of the University much greater kidney dysfunction than wild type counterparts. Con- of Lausanne, where she was then nominated as extraordinary profes- versely, treatment of wild–type C57BL/6 mice with a PPARbeta ligand sor in 1996 and associate professor in 1999. She also holds a bachelor L–165041 remarkably prevented the ischemia/reperfusion–depen- degree in Philosophy. She joined the Center for Integrative Genomics dent glomerular and tubular dysfunction. Further analyses performed in 2003. on HK–2 cells in culture indicated that exposure to a PPARbeta ligand reshape the cells, with flattening and spreading that have been shown

30 CIG 2005/2006 Group Publications

GROUP LEADER Research articles Genolet R, Kersten S, Brais- accommodate variations in spec- Nadra K, Anghel SI, Joye E, obesity, and type 2 diabetes. Cell Béatrice Desvergne sant O, Mandard S, Tan NS, tral bleed–throughs. Microsc Res Tan NS, Basu–Modak S, Trono Metab 4 : 407–414 [email protected] Di–Poï N, NG CY, Tan NS, Des- Bucher P, Desvergne B, Mi- Tech 68 : 51–58 D, Wahli W, Desvergne B vergne B,Michalik L, Wahli W chalik L, Wahli W (2005) (2006) Wang D, Wang H, Guo Y, TECHNICIANS (2005) Promoter rearrangements cause Debril MB, Dubuquoy L, Feige Differentiation of trophoblast Ning W, Katkuri S, Wahli W, Elisabeth Joye Epithelium–mesenchyme species–specific hepatic regula- J, Wahli W, Desvergne B, giant cells and their metabolic Desvergne B, Dey SK, Dubois Geneviève Metthez interactions control the activity tion of the glyoxylate reductase/ Auwerx J, Gelman L (2005) functions are dependent on RN (2006) of PPARbeta/delta during hair hydroxypyruvate reductase gene Scaffold attachment factor B1 peroxisome proliferator–activa- Crosstalk between peroxisome MAITRE–ASSISTANT follicle development. Mol Cell by the peroxisome proliferator– directly interacts with nuclear ted receptor beta/deltA. Mol Cell proliferator–activated receptor Laurent Gelman* Biol 25 : 1696–1712 activated receptor alphA. J Biol receptors in living cells and Biol 26 : 3266–3281 {delta} and VEGF stimulates can- Chem 280 : 24143–24152 represses transcriptional activity. cer progression. Proc Natl Acad POSTDOCTORAL FELLOWS Tan NS, Michalik L, Desvergne J Mol Endocrinol 35 : 503–517 Varnat F, Bordier–ten Heg- Sci USA 103 : 19069–19074 Elodie Bedu B, Wahli W (2005) Michalik L, Feige JN, Gelman geler B, Grisel P, Boucard N, Jérôme Feige Genetic– or TGF–beta 1–induced L, Pedrazzini T, Keller H, Des- Di–Poï N, Desvergne B, Mi- Corthésy–Theulaz I, Wahli W, continued on next page >>> Karim Nadra* changes in epidermal PPARbeta/ vergne B, Wahli W (2005) chalik L, Wahli W (2005) Desvergne B (2006) Frédéric Varnat delta expression dictate wound Selective expression of a domi- Transcriptional repression of PPARbeta/delta regulates Paneth repair kinetics. J Biol Chem 280 : nant negative form of PPAR in peroxisome proliferator–activa- cell differentiation via controlling PhD STUDENTS 18163–18170 keratinocytes leads to impaired ted receptor beta/delta in murine the hedgehog signaling pathway. Imtiyaz Ahmad epidermal healing. Mol. Endocri- keratinocytes by CCAAT/enhan- Gastroentrology 2006 131 : Jean–Marc Brunner Feige JN, Gelman L, Tudor nol. 19 : 2335–2348 cer–binding proteins. J Biol Chem 538–553 Alan Gerber C, Engelborghs Y, Wahli W, 280 : 38700–38710 He Fu Desvergne B (2005) Metzger D, Imai T, Jiang M, Knauf C, Rieusset J, Foretz M, Matthew Hall Fluorescence imaging reveals the Takukawa R, Desvergne B, T he Eumorphia Consortium : Cani PD, Uldry M, Hosokawa Sajit Thottathil Oommen nuclear behavior of PPAR/RXR Wahli W, Chambon P (2005) Authors from the Center for M, Martinez E, Bringart M, heterodimers in the absence and Functional role of RXRs and Integrative Genomics : Wahli Waget A, Kersten S, Desver- MASTER STUDENTS presence of ligand. J Biol Chem PPARgamma in mature adipocy- W, Delgado MB, Desvergne B, gne B, Gremlich S, Wahli W, Daniel Rossi* 280 : 17880–17890 tes. Prostaglandins Leukot Essent Michalik L, Bedu E (2005) Seydoux J, Delzenne NM, Beatriz Tavera Tolmo* Fatty Acids 73 : 51–58 EMPReSS : standardised pheno- Thorens B, Burcelin R (2006) Rousseaux C, Lefebvre B, type screens for functional anno- PPAR{alpha} null mice have ADMINISTRATIVE Dubuquoy L, Lefebvre P, Ro- Letavernier E, Perez J, Joye E, tation of the mouse genome. Nat increased white adipose tissue ASSISTANT mano O, Auwerx J, Metzger Bellocq A, Fouqueray B, Hay- Genet 37 : 1155 glucose utilization, GLUT4, and Marlène Petit D, Wahli W, Desvergne B, mann JP, Heudes D, Wahli W, fat mass Role in liver and brain. Joanna Schwab* Naccari GC, Chavatte P, Farce Desvergne B, Baud L (2005) A li FY, Egan K, Fitzgerald Endocrinology 147 : 4067–4078 A, Bulois P, Cortot A, Colom- PPARbeta/delta exerts a strong GA, Desvergne B, Wahli W, *left the group bel JF, Desreumaux P (2005) protection from ischemic acute Bishop–Bailey D, Warner TD, Schuler M, Ali F, Chambon C, Intestinal antIInflammatory renal failure. J Am Soc Nephrol Mitchell JA (2006) Duteil D, Bornert JM, Tardivel effect of 5–aminosalicylic acid 16 : 2395–2402 Role of prostacyclin receptor A, Desvergne B, Wahli W, is dependent on peroxisome versus PPAR–beta with trepros- Chambon P, Metzger D (2006) proliferator–activated recep- Feige JN, Sage D, Wahli W, tinil sodium on lung fibroblast PGC1alpha expression is tor–{gamma}. J Exp Med 201 : Desvergne B, Gelman L (2005) proliferation. Am J Respir Cell controlled in skeletal muscles 1205–1215 PixFRET, an ImageJ plug–in Mol Biol 34 : 242–246 by PPARbeta, whose ablation for FRET calculation which can results in fiber–type switching,

31 Publications (continued) Collaborations

Review articles Gelman L, Feige JN, Tudor L. Baud and E. Letavernier, C, Engelborghs Y, Wahli W, INSERM, Paris, France Gelman L, Michalik L, Desver- Desvergne B (2006) M. Crestiani, gne B, Wahli W (2005) Integrating nuclear receptor mo- University of Milan, Italy Kinase signaling cascades that bility in models of gene regula- modulate peroxisome prolife- tion. Nucl Recept Signal 4 : e010 S. Dedhar, rator–activated receptors. Curr British Columbia Research Center, Vancouver, Canada Opin Cell Biol 17 : 216–222 Letter to the editor, P. Desreumaux, Book chapter Dubuquoy L and chamaillard E, Université de Lille, France Tan NS, Michalik L, Desvergne B, Wahli W (2005) Varnat F, Desvergne B (2006) S. K. Dey and R. Dubois, Multiple expression control A cautionnary note – Letter and Vanderbilt University Medical Center and Vanderbilt–Ingram Cancer Center, Nashville, USA mechanisms of peroxisome reply–. Gastroenterology Y. Enghelborgs, proliferator–activated receptors 131 : 1658–1659 Université de Leuven, Belgique and their target genes. J Steroid Biochem Mol Biol 93 : 99–105 Varnat F, Michalik L, Desver- F. Gonzalez, gne B, Wahli W (2006) National Cancer Institute, Bethesda, USA Bedu E, Wahli W, Desvergne PPARs : lipid sensors that regu- M. Janier and M. Wiart, B (2005) late cell differentiation processes. CNRS Plateforme Animage, Lyon, France Peroxisome proliferator–acti- In : Nutritional Genomics : Impact vated receptor beta/delta as a on Health and Disease; Brige- R. Métivier, therapeutic target for metabolic lius–Flohé R and Joost HG eds; Université de Rennes, France diseases. Expert Opin Ther Tar- Wiley–VCH Verlag GmbH & Co D. Metzger and P. Chambon, gets 9 : 861–873 KGaA, Weinheim Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch–Strasbourg, France Feige JN, Gelman L, Micha- J. A. Mitchell, lik L, Desvergne B, Wahli W Imperial College London, London, UK (2006) L. Nagy, From molecular action to University of Debrecen, Hungary physiological outputs : peroxisome proliferator–activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog Lipid Res 45 : 120–159

Desvergne B, Michalik L, Wahli W (2006) Transcriptional control of metabolism. Physiol Rev 86 : 465–514

32 CIG 2005/2006 33 Research | The genomics of complex functions

Liliane Michalik Roles of PPARs in skin biology Group Publications Maître d’enseignement et de recherche and angiogenesis

The skin is a barrier that protects the organism from various insults. Group leader Research articles Due to its peripheral localization, it is prone to be damaged, for Liliane Michalik instance by mechanical injury or UV radiations. The repair process after [email protected] Gremlich S, Nolan C, Roduit R, an injury is a life–saving process that involves keratinocytes, immune Burcelin R, Peyot ML, Del- cells, fibroblasts and blood vessels. The molecular mechanisms and Technician ghingaro-Augusto V, Desver- cell functions implicated in repair share many common characteristics Cécile Duléry gne B, Michalik L, Prentki M, with the uncontrolled development of skin cancers. We are interested Wahli W (2005) in understanding the roles of the nuclear receptors PPARs as transcrip- PhD students Pancreatic islet adaptation to fas- tional regulators of skin repair, UV induced carcinogenesis and angio- Raphaël Terrier ting is dependent on PPARalpha genesis. As a model system, we use various mouse lines in which the Marta Wawrzyniak transcriptional up-regulation of expression of PPARs is modified, as well as Xenopus laevis. We have fatty acid oxidation. Endocrino- observed that the wound healing process is delayed in the absence of logy 146:375-382 PPARbeta, and that PPARbeta controls many properties of the keratinocytes that are essential for rapid wound closure. Our current interest Skrtic S, Carlsson L, Ljung- is to understand the role of PPARs in the other cell types involved in berg A, Lindén D, Michalik L, skin repair and in the development of skin carcinomas, with a particu- Wahli W, Oscarsson J (2005) lar focus on angiogenesis. Decreased expression of PPARal- pha and liver fatty acid binding protein after partial hepatectomy of rats and mice. Liver Int 25:33-40

Planavila A, Rodriguez-Calvo R, Jové M, Michalik L, Wahli W, Laguna JC, Vàzquez-Car- rera M (2005) Peroxisome proliferator-activated receptor beta/delta activation Liliane Michalik received her PhD from the University Louis Pasteur of inhibits hypertrophy in neonatal Strasbourg, France, in 1993. She then was a postdoctoral fellow in the rat cardiomyocytes. Cardiovasc lab of Walter Wahli at the University of Lausanne, where she started Res 65:832–841 a research project aimed at elucidating the roles of the nuclear hormone receptor PPARs in skin homeostasis and repair. Between 1996 Di-Poï N, Ng CY, Tan NS, Yang and 2002, she was maître assistant at the Institute for Animal Biology Z, Hemmings BA, Desvergne and then joined the Center for Integrative Genomics in 2003 as maître B, Michalik L, Wahli W (2005) d’enseignement et de recherche. Epithelium-mesenchyme interactions control the activity of PPARbeta/delta during hair follicle development. Mol Cell Biol 25:1696-1712

34 CIG 2005/2006 Collaborations

Tan NS, Michalik L, Desvergne Reciprocal regulation of brain Feige JN, Gelman L, Micha- Book chapters S. Werner, B, Wahli W (2005) and muscle Arnt-like protein 1 lik L, Desvergne B, Wahli W Swiss Federal Institute of Technology Zurich (ETHZ), Switzerland Genetic- or TGF-beta 1-induced and peroxisome proliferator-ac- (2006) Varnat F, Michalik L, D. Hohl, changes in epidermal PPARbeta/ tivated receptor alpha defines a From molecular action to phy- Desvergne B, Wahli W (2006) Centre Hospitalier Universitaire (CHUV), Lausanne, Switzerland delta expression dictate wound novel positive feedback loop in siological outputs: Peroxisome PPARs: lipid sensors that regulate repair kinetics. J Biol Chem the rodent liver circadian clock. proliferator-activated receptors cell differentiation processes. In: O. Michielin and V. Zoete, 280:18163-18170 Mol Endocrinol 20:1715-1727 are nuclear receptors at the Nutritional Genomics: Impact on Swiss Institute for Bioinformatics, Lausanne, Switzerland crossroads of key cellular func- Health and Disease; Brigelius- M. Swartz, Genolet R, Kersten S, Brais- Review articles tions. Prog Lipid Res 45:120-159 Flohé R and Joost HG eds; Wiley- EPFL (Ecole Polytechnique Fédérale de Lausanne), Switzerland sant O, Mandard S, Tan NS, VCH Verlag GmbH & Co. KGaA, Bucher P, Desvergne B, Mi- Gelman L, Michalik L, Icre G, Wahli W, Michalik L Weinheim D. Dombrowicz, chalik L, Wahli W (2005) Desvergne B, Wahli W (2005) (2006) Institut Pasteur de Lille, France Promoter rearrangements cause Kinase signaling cascades that Functions of the Peroxisome Michalik L, Wahli W (2006) Institut de recherche Pierre Fabre Dermo-cosmétique, species-specific hepatic regula- modulate peroxisome prolife- Proliferator-Activated Receptor PPARs and colon cancers : A Toulouse, France tion of the glyoxylate reductase/ rator-activated receptors. Curr (PPAR) alpha and beta in skin curse or a cure? In: Recent hydroxypyruvate reductase gene Opin Cell Biol 17:216-222 homeostasis, epithelial repair, Advances in Gastrointestinal Bioresearch and Partners, by the peroxisome proliferator- and morphogenesis. J Invest Carcinogenesis; Bamba H and Monthey, Switzerland activated receptor alpha. J Biol Tan NS, Michalik L, Desvergne Dermatol 126 Suppl:30-5 Ota S eds; Transworld Research Chem 280:24143-24152 B, Wahli W (2005) Network, India Multiple expression control Lathion C, Michalik L, Wahli Michalik L, Feige JN, Gelman mechanisms of peroxisome W (2006) L, Pedrazzini T, Keller H, Des- proliferator-activated receptors Physiological ligands of PPARs in vergne B, Wahli W (2005) and their target genes. J Steroid inflammation and lipid homeos- Selective expression of a domi- Biochem Mol Biol 93:99-105 tasis. Future Lipidology 1:191-201 nant negative form of PPAR in keratinocytes leads to impaired Kostadinova R, Wahli W, Desvergne B, Michalik epidermal healing. Mol Endocri- Michalik L (2005) L, Wahli W (2006) nol 19:2335-2348 PPARs in disease : control mecha- Transcriptional regulation of me- nisms of inflammation. Curr Med tabolism. Physiol Rev 86:465-514 Di-Poï N, Desvergne B, Micha- Chem 12:2995-3009 lik L, Wahli W (2005) Michalik L, Wahli W (2006) Transcriptional repression of Michalik L, Auwerx J, Berger Involvement of PPAR nuclear peroxisome proliferator-activated JP, Chatterjee VK, Glass CK, receptors in tissue injury and receptor beta/delta in murine Gonzalez FJ, Grimaldi PA, wound repair. J Clin Invest keratinocytes by CCAAT/enhan- Kadowaki T, Lazar MA, O’ra- 116:598-606 cer-binding proteins. J Biol Chem hilly S, Palmer CN, Plutzky J, 280:38700-38710 Reddy JK, Spiegelman BM, Rotman N, Michalik L, Staels B, Wahli W (2006) Desvergne B, Wahli W (2006) Canaple L, Rambaud J, International Union of Phar- PPARs in fetal and early postna- Dkhissi-Benyahya O, Rayet B, macology. LXI. Peroxisome tal development. Advances in Tan NS, Michalik L, Delaunay Proliferator-Activated Receptors. Developmental Biology 16 F, Wahli W, Laudet V (2006) Pharmacol Rev 58:726-741

35 Research | The genomics of complex functions

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

Glucose homeostasis and development of type 2 diabetes are critically In a third line of investigation, we analyze the changes in gene expres- regulated by the capacity of the insulin secreting beta–cells of the pan- sion in liver and adipose tissues of mice with different genetic back- creas to secrete insulin according to the metabolic need of the orga- ground and fed high fat diets to identify the changes in metabolic nism. This secretory capacity depends on both the mass and function activity that underlie sensitivity or resistance to obesity development. of the differentiated beta–cells. These studies make extensive use of the microarray technologies provided by the DNA Array and Metabolic facilities of the CIG. One of our research project is to search for genes that are under the control of GLP–1 and GIP, two hormones that control the differentiation of pancreatic beta–cells from precursor cells, the proliferation of mature beta–cells and their protection against apoptosis. This search is based on transcriptomic analysis of genes expressed in islet cells in which the action of these two hormones has either been suppressed by gene knockout or, in contrast, activated by exposure of the cells to these hormones. The function of these genes is investigated by overex- pression or down–expression (siRNA) studies in beta–cell lines, primary beta cells and in transgenic mice, followed by functional analysis of proliferation, apoptosis, and insulin secretion.

Glucose homeostasis, feeding behavior and energy expenditure are also under the control of the hypothalamus, where neuronal circuits integrate internal signals, informing on food absorption and storage of metabolic energy, and send new signal to regulate energy homeostasis.

In this second line of investigation we 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 knock- Bernard Thorens received his PhD in Geneva in 1984 for studies carried out mice, which show loss of central glucose sensing and, as a conse- in the laboratory of Pierre Vassalli. He then did a postdoctoral fellow- quence, deregulated control of feeding and energy expenditure. These ship at the Whitehead Institute for Biomedical Research in Cambridge, studies are being pursued by genetically marking the glucose sensing UK, with Harvey Lodish. In 1991 he received a Career Development cells to identify them and characterize the neuronal circuits they form. Award from the Swiss National Science Foundation to establish his Transcriptomic analysis have also been performed to identify the set of research group at the Department of Pharmacology and Toxicology of genes that are regulated by these glucose sensing cells to identify novel the University of Lausanne. Since 2002 he is Professor of Physiology at molecular mechanisms of controlling feeding and energy expenditure. the University and since November 2005, he is working at the CIG. These investigations involve the use of molecular biology techniques, immunohistochemistry, in situ hybridization, and integrated physiological analysis of control or genetically modified mice.

36 CIG 2005/2006 Group Publications Collaborations

GROUP LEADER Research articles Marty N, Bady I, Thorens B Review articles / M. Donath, Bernard Thorens (2006) Editorials University Hospital Zurich, Switzerland [email protected] since B. Thorens arrival at the Distinct classes of central C. Wollheim and P. Halban, CIG (November 2005) GLUT2–dependent sensors Thorens B (2006) University of Geneva, Switzerland BIOINFORMATICIAN control counterregulation and A missing sugar prevents glucose Carine Poussin Widmer M, Uldry M, Tho- feeding. Diabetes 55 Suppl 2 : entry : A new twist on insulin All labs involved in the European projects HEPADIP & EURODIA rens B (2005) S108–113 secretion. Cell Metab 3 : 3–5 TECHNICIANS GLUT8 subcellular localization Wanda Dolci and absence of translocation to Tweedie E, Artner I, Crawford Thorens B (2006) Martine Emery the plasma membrane in PC12 L, Poffenberger G, Thorens B, A toggle for type 2 diabetes? N Joël Gyger cells and hippocampal neurons. Stein R, Powers AC, Gannon Engl J Med 354 : 1636–1638 David Tarussio Endocrinology 146 : 4727–4736 M (2006) Maintenance of hepatic nuclear Thorens B (2006) POSTDOCTORAL FELLOWS Marty N, Dallaporta M, Fo- Factor 6 in postnatal islets im- L’axe entéro–insulaire : rôle de Isabelle Bady* retz M, Emery M, Tarussio D, pairs terminal differentiation and l’intestin et régulation glycémi- Marie–Bernard Debril Bady I, Binnert C, Beermann function of beta–cells. Diabetes que. Journ Annu Diabetol Hotel Diana Hall F, Thorens B (2005) 55 : 3264–3270 Dieu 2006 : 67–73 Maria Jimenez Regulation of glucagon secretion Fabrice Marcillac by glucose transporter type 2 Knauf C, Rieusset J, Foretz M, Matthieu Membrez* (glut2) and astrocyte–dependent Cani PD, Uldry M, Hosokawa Lourdes Mounien glucose sensors. J Clin Invest. M, Martinez E, Bringart M, Pascal Seyer 115 : 3545–3553 Waget A, Kersten S, Desver- gne B, Gremlich S, Wahli W, PhD STUDENTS Bady I, Marty N, Dallaporta Seydoux J, Delzenne NM, Marion Cornu M, Emery M, Gyger J, Tarussio Thorens B, Burcelin R (2006) Sonia Klinger D, Foretz M, Thorens B (2006) Peroxisome proliferator–activa- Nell Annette Marty Evidence from glut2–null mice ted receptor–alpha–null mice Yann Ravussin* that glucose is a critical phy- have increased white adipose Audrey Sambeat siological regulator of feeding. tissue glucose utilization, GLUT4, Diabetes 55 : 988–995 and fat mass : Role in liver and MASTER STUDENT brain. Endocrinology 147 : Gilles Willemin* Membrez M, Hummler E, 4067–4078 Salima Metref Beermann F, Haefliger J–A, Savioz R, Pedrazzini T, Tho- ADMINISTRATIVE rens B (2006) ASSISTANTS GLUT8 is dispensable for Claudia Hoffmann–Denarié embryonic development but Christine Winkler* influences hippocampal neuro- Monique Laverrière–Schultz* genesis and heart function. Mol Cell Biol 26 : 4268–4276 *left the group

Core2) Research facilities Core facilities | DNA array facility – DAF

Keith Harshman DNA Array Facility (DAF) Group Coordinator of the facility Maître d’enseignement et de recherche

The primary goal of the Lausanne DNA Array Facility (DAFL) is to pro- GROUP LEADER vide the user community with access to the state–of–the–art technolo- Keith Harshman gies as well as bioinformatic protocols used to detect, measure and [email protected] analyze quantitative and qualitative variations in nucleic acids. The principal technology platforms supported by the DAFL to achieve this goal COORDINATOR are the Affymetrix GeneChip oligonucleotide array platform, in–house AFFYMETRIX PLATFORM spotted cDNA and oligonucleotide arrays as well as quantitative real– Otto Hagenbüchle time PCR. The DAFL provides users with training and supervision in all aspects of the molecular biology and instrument manipulations associ- COORDINATOR ated with DNA microarray experiments. In many cases, the DAFL will MICROARRAYS and qPCR perform all of the steps of the array experiment, beginning with RNA PLATFORMS provided by the user. The facility provides access to and training in the Johann Weber use of the instrumentation and the consumables that are required to perform quantitative real–time PCR analyses using the Applied Biosys- BIOINFORMATICIANS tems 7900HT Sequence Detection System. The DAFL provides bioinfor- Sylvain Pradervand matics support and consultation services at the stages of experimental Darlene Goldstein design, data collection and storage, image analysis and, when appro- Beate Sick* priate, higher level data analysis. To support these bioinformatic activi- Gnanasekaran Thoppae* ties, the DAFL has a close collaboration with the Bioinformatic Core Facility of the NCCR Molecular Oncology Program. The DAFL also sup- TECHNICIANS ports users in the production and use of protein microarrays and in the Manuel Bueno use of commercial array platforms designed for analyzing microRNA Alexandra Paillusson gene expression. The facility allows users to carry out their experiments Jérôme Thomas in its laboratories by providing equipment and bench space. Further- Sophie Wicker more, the DAFL maintains computer workstations and software with which users can analyze their data. ADMINISTRATIVE ASSISTANT Fabienne Sauvain Keith Harshman received his PhD in Biochemistry from the California Institute of Technology, USA, in 1990. Following post doctoral fellow- *left the group ships at the University of Zurich and the Sloan–Kettering Cancer Cen- ter, in 1993 he joined Myriad Genetics Inc. where he worked first as a Senior Scientist and later as the Director of Central Nervous System Dis- ease Research. In 1997 he moved to the Department of Immunology & Oncology of the National Biotechnology Center in Madrid, Spain, as the Head of the Functional Genomics Unit. He has been the Coordina- tor of the Lausanne DNA Array Facility since November of 2002.

40 CIG 2005/2006 Collaborations

In 2005 and 2006, the DAF provided support for numerous projects from departments of the Faculty of Biology and Medicine of the UNIL and from the Centre Hopsitalier Universitaire Vaudois (CHUV), the Swiss Institute for Experimental Cancer Research (ISREC) and the EPFL (Ecole Polytechnique Fédérale de Lausanne) in Lausanne. Also, several projects came from other swiss universities (Geneva, Neuchâtel, Zurich).

41 Core facilities | Protein analysis facility – PAF

Manfredo Quadroni Protein Analysis Facility (PAF) Coordinator of the facility Maître d’enseignement et de recherche

Proteomics is becoming a viable approach to study the organization Alternatively, we also tackle the characterization of proteins which of complex cellular pathways. By combining labeling and separation share a common targeting fate and as such are also functionally cor- techniques with high–throughput mass spectrometry, it is now pos- related. So we have performed differential analysis of proteins pre- sible to analyze complex protein mixtures to determine their compo- sent in lipid rafts on the surface of several melanoma cell lines, with the sition and detect changes associated with a given biological process. goal to establish possible correlations with the varying invasive phe- This approach is most promising to analyze fractions of proteins that notype of these cells (with C. Ruegg, Swiss Institute for Experimen- are connected by a functional relationship, typically by direct interac- tal Cancer Research (ISREC)/Multidisciplinary Oncology Center (CePO), tion (formation of a supramolecular complex) or co–localization to a Lausanne). Also with the group of M. Monod, (Centre Hospitalier Uni- functionally defined cellular compartment. versitaire Vaudois (CHUV), Lausanne), we have undertaken the comprehensive identification of the proteins secreted (the “secretome”) by 1) Independent technology development projects : We are pursu- the two skin infecting fungi Trychophyton rubrum and Trychophyton ing the development of a technique to specifically identify in complex violaceum. This fraction is highly enriched in proteases, which play a mixtures such as whole cell extracts the proteins that were synthesized role in the invasion of the skin layers. at high rates during a given time. This approach will be based on metabolic labeling of cell cultures with stable isotope derivatives of amino acids (SILAC) and a specific detection by mass spectrometry of frag- ments of these proteins that have incorporated the label. We have pre- liminary evidence showing the viability of the approach in a biological system (infection of cells with Herpes Simplex virus). In addition, we are developing a novel method for relative protein quantification based on the same labeling scheme.

On the software side, we have collaborated with the Swiss Institute of Bioinformatics (SIB) in Geneva (group of R. Appel) to create and test MSIGHT, a freeware software for the representation and comparison of liquid–chromatography–mass spectrometry data (www.expasy. org/msight).

Manfredo Quadroni got his PhD in Biochemistry at the Swiss Federal 2) Collaborative studies on functionally related sets of pro- Institute of Technology Zurich (ETHZ) in 1996. He completed his first teins : We have several research efforts based on collaborations. These postdoctoral training at the University of British Columbia, Canada, in project are mainly focusing on the analysis of complexes of interac- the group of Prof. J. Schrader, with focus on the proteomics analysis of ting proteins. We have been able to map extensively the proteins bin- cell signalling complexes in immunology, and his second postdoctoral ding to RelA (an important member of the NF–kappaB family) through training at Swiss Federal Institute of Technology Zurich (ETHZ) (1998– its transcription activation domain (with M. Hottiger, Zurich). We are 2000) focused on development of methods for proteome analysis. He also studying both the post–translational processing and the molecules was then Maître assistant at the Institute of Biochemistry of the Univer- interacting with two novel death–domain–containing proteins named sity of Lausanne between 2000 and 2003. He joined the CIG in March PIDD and ZUD, whose function was until recently unknown (with J. 2003 as maître d’enseignement et de recherche (MER) to coordinate Tschopp, University of Lausanne). We have also an ongoing project on the PAF facility. the characterization of the SCF–like ubiquitin ligase complexes formed around Cullin–3 and Cullin–4A in human cells (with M. Peter, Swiss Federal Institute of Technology Zurich (ETHZ)).

42 CIG 2005/2006 Group Publications Collaborations

Group leader Research articles Walker J, Acestor N, Gongora J.–J. Diaz and A. Greco, Manfredo Quadroni R, Quadroni M, Segura I, Fasel INSERM, Lyon, France [email protected] Palagi PM, Walther D, Qua- N, Saravia NG (2006) M. Hottiger, droni M, Catherinet S, Bur- Comparative protein profiling University of Zurich, Switzerland Coordinator at the CIG gess J, Zimmermann–Ivol CG, identifies elongation fac- Patrice Waridel Sanchez JC, Binz PA, Hochs- tor–1beta and tryparedoxin J. Tschopp, trasser DF, Appel RD (2005) peroxidase as factors associated University of Lausanne, Switzerland Bioinformatician MSight : an image analysis with metastasis in Leishmania M. Peter, Gnanasekaran Thoppae software for liquid chromato- guyanensis. Mol Biochem Parasi- Swiss Federal Institute of Technology Zurich (ETHZ), graphy–mass spectrometry. tol 145 : 254–264 Switzerland Technicians Proteomics 5 : 2381–2384. Jachen Barblan * equal contribution C. Ruegg, Alexandra Potts O, Quadroniwen HR* M*, Centre Hospitalier Universitaire (CHUV) Bienvenut W, Buerki C, Hotti- and University of Lausanne, Switzerland Postdoctoral fellow ger MO (2005) M. Monod, Willy Bienvenut* Identification of novel and cell Centre Hospitalier Universitaire (CHUV) and type enriched cofactors of the University of Lausanne, Switzerland PhD student transcription activation domain Mara Colzani of RelA (p65 NF–kappaB). J Pro- teome Res 4 : 1381–1390 *left the group Arrigoni G, Resjo S, Levander F, Nilsson R, Degerman E, Quadroni M, Pinna LA, James P (2006) Chemical derivatization of phos- phoserine and phosphothreonine containing peptides to increase sensitivity for MALDI–based analysis and for selectivity of MS/MS analysis. Proteomics 6 : 757–766

43 Core facilities | Core facilities associated with the CIG

Vital-IT The Cellular Imaging Facility (CIF)

COORDINATOR : COORDINATOR: V. Jongeneel Jean–Yves Chatton [email protected] [email protected]

Vital-IT is an innovative life science informatics initiative providing com- THE MAIN ACTIVITIES UNDERTAKEN BY VITAL-IT ARE : Technical manager at the CIG: putational resources, consultancy and training to connect fundamental Arnaud Paradis and applied research. It is a collaboration between the Swiss Institute of • Providing an HPC environment to support the research work of its Bioinformatics (SIB), the Universities of Lausanne and Geneva, the Lud- partners, in areas ranging from sequence analysis through molecu- The Cellular Imaging Facility (CIF) was created in 2003 initially as the wig Institute for Cancer Research (LICR), the EPFL (Ecole Polytechnique lar modeling to large–scale data management. result of a joint financial and structural effort of the Faculty of Biol- Fédérale de Lausanne), Hewlett Packard Company, Intel Corporation ogy and Medicine of the University of Lausanne and the University and Oracle. These partners form an alliance of unrivalled expertise in • Developing specialist software engineering techniques for paral- Hospital (Hospices/CHUV) and located in the Medical School build- the processing and analysis of biological information. Using their com- lelization, optimization and validation of complex algorithms, and ing. Since Summer 2005, the CIF is also present on the Dorigny cam- plementary competencies, they provide fundamental science and lead- their implementation on specialized hardware. pus, at the CIG building and in the Biology building. The operations ing edge technology for the construction of a world–class high–perfor- are overseen by a Steering Committee, with both strategic and scien- mance computing platform, and the expertise to allow it to be exploited • Development activities to turn concepts derived from research into tific responsibilities, representing all involved institutions in addition to effectively for solution of both scientific and commercial problems. robust software solutions. external partners. The mission of the CIF is to assist researchers with imaging needs ranging from wide–field fluorescence and transmission • Consulting and educational activities geared towards the computa- Vital-IT provides infrastructure and computational expertise to support optical microscopy, confocal microscopy, time–lapse and ion imaging, tional needs of companies in the life sciences. research conducted primarily by its partners, and develops hardware to digital image processing and analysis. The CIF is organized around and software solutions to allow research results to be turned into mar- • Acting as an agent for new collaborations with industry and in three complementary activities : (a) service activities : investigators are ketable products. Additionally, the group serves as an interface between future, including potential spin–off of new companies in the field offered access to a panel of state–of–the–art imaging equipment and academic research and its consumers in the commercial world. of life–science informatics. techniques; (b) teaching and Training : the CIF shares and diffuses the practical and theoretical know–how on these approaches through WEBSITE : teaching and training to researchers, technicians, as well as pre– and http : //www.vital-it.ch post–graduate students; (c) research and technological development performed by investigators affiliated with the CIF who develop and implement most advanced optical and imaging technologies, eventu- ally rendered accessible to more users of the CIF.

WEBSITE http : //www2.unil.ch/cif/

44 CIG 2005/2006 The Bioinformatics Core Facility (BCF) The Mouse Metabolic Evaluation Center for Investigation Facility (MEF) and Research on Sleep (CIRS)

COORDINATOR: DIRECTOR: CO-DIRECTOR: Mauro Delorenzi Bernard Thorens Mehdi Tafti (CIG), with Raphaël Heinzer (Centre Hospitalier [email protected] [email protected] Universitaire Vaudois, CHUV) [email protected] The Bioinformatics Core Facility (BCF) is part of the Swiss National COORDINATOR: Fund funded NCCR Molecular Oncology program at Swiss Institute for Frédéric Preitner Sleep disorders are very prevalent, and represent an “emerging world- Experimental Cancer Research (ISREC). Its mission falls into four ge- [email protected] wide epidemic”. However, despite an impressive progress during the neral areas : last 3 decades, biological and molecular bases of most sleep disorders The Mouse Metabolic Evaluation Facility (MEF) was created in 2006 as remain unknown. Consequently, almost all available treatments for a) Service : provide basic bioinformatic and data analytic support the result of a joint financial and structural effort of the Center for Inte- sleep disorders are symptomatic and not evidence-based. Given their at all stages of gene expression and other high throughput grative Genomics, the University Hospital in Lausanne (CHUV) and the variety and impact on different biological systems (respiration, metabo- studies, from design to data acquisition, analysis, and interpre- NCCR Frontiers in Genetics. The MEF is located at CIG. lism, motor control, cognition), a multidisciplinary approach is needed, tation, with a focus on clinical and cancer–related projects; not only for understanding the pathophysiology but also for diagnosis The mission of the MEF is to provide the Lausanne and swiss research and treatment of sleep disorders. Thus, in collaboration with clinicians b) Education : train groups carrying out NCCR–supported pro- community with a wide repertoire of state–of–the–art, standardized specialist in sleep disorders, we have established the Center for Inves- jects in the application and interpretation of basic methods of investigative techniques to analyze the metabolic status of mice models tigation and Research on Sleep (CIRS). This joint venture between the data analysis through course and workshop offerings; of complex human disorders. CIG and the Centre Hospitalier Universitaire (CHUV), Lausanne, provides a state-of-the-art infrastructure to conduct high level basic and c) Collaboration : participate as collaborators for projects requir- Given the high level of complexity of most techniques, the MEF provides clinical research and to offer to the community the highest standard for ing advanced or individualized attention; services to the researchers. The MEF also provides teaching for those diagnosis and treatment of sleep disorders. who want to introduce specific techniques into their own laboratories. d) Research : have an active research program to advance me- In order to broaden the scope of phenotyping tests, the MEF aims also The CIRS was officially inaugurated in January 2007. thodological developments in the analysis of gene expression at developing new investigation techniques in partnership with labora- data and integration of these with other biological data, par- tories at University of Lausanne, at the Centre Hospitalier Universitaire ticularly to study the association of expression patterns with Vaudois (CHUV) and EPFL (Ecole Polytechnique Fédérale de Lausanne) clinical and survival data; The MEF is an integral part of the CHUV–UNIL CardioMet research center that gathers three coordinated investigative units, namely the The BCF “headquarter” is at the CIG with offices also at Swiss Institute MEF, the Rodent Cardiovascular Phenotyping Center (coordinated by for Experimental Cancer Research (ISREC) in Epalinges. Prof. Thierry Pedrazzini, at the UNIL) and the Clinical Investigation Cen- ter (coordinated by Prof. François Pralong at CHUV). CardioMet aims at WEBSITE fostering joint projects in clinical and basic research, in the cardiovascu- http : //www.isrec.isb-sib.ch/BCF/ lar and metabolic fields.

WEBSITE http : //www.unil.ch/cig/page41381.html

45 education Education | Lectures and courses

The Student Program Lectures And Courses Given By The CIG Members

Education is central to the mission of the CIG. The master BACHELOR COURSES Structure des génomes des végétaux The CIG members give lectures, seminars and practical courses in the The CIG is principally involved in the UNIL Master of Science in Geno- Henrik Kaessmann School of Biology of the Faculty of Biology and Medicine of the Univer- mics and Experimental Biology (GBE). This program is designed for stu- Evolution moléculaire N ouria Hernandez, Winship sity of Lausanne, teach in other institutions, and organize workshops dents who are curious, motivated, and enthusiastic about the explora- Herr, Christian Fankhauser, and courses. The group leaders mentor master and PhD students in tion of life through the application of experimental biology methods Alexandre Reymond Victor Jongeneel their research, and also participate in an additional academic mentor- and the new field of genomics. The master degree courses aim at pro- Statistiques pour biologistes Cartographie, séquençage et ing program. viding key expertise required in this field. On the one hand, the train- structure des génomes ing provides an in–depth knowledge of genetics and molecular biolo- Mehdi Tafti, Winship Herr, Learning and interacting with other scientists is an essential compo- gy, offering specialized courses on the interactions of molecules within Alexandre Reymond Mehdi Tafti nent of a researcher’s life all along her/his career. The CIG thus arran- networks that control the life of micro–organisms, plants and animals. Du génome au phénome et du Neuroscience ges regular presentations by external speakers: during the academic On the other hand, considerable attention is dedicated to the learning phénome au génome term, a weekly CIG/Génopode seminar–series is organized. Besides a and application of advanced techniques in genome annotation, gene Paul Franken, Keith Harsh- scientific presentation by the speaker, this seminar–series is also the expression analysis and bioinformatics. Nouria Hernandez, man, Manfredo Quadroni occasion for interactions at several levels: all participants meet after the Walter Wahli (with Johann Weber) presentation around a sandwich lunch, and special time is dedicated The faculty member coordinating the Master of Science in Genomics Transcription et maturation de Genomics, proteomics and quan- for a discussion between the speaker and students and postdocs, and and Experimental Biology (GBE) is Christian Fankhauser who succeeded l’ARN titative genetics for a dinner with the invited speaker and CIG/Génopode faculty mem- Liliane Michalik in September 2005. bers and others. Béatrice Desvergne Walter Wahli The PhD program Biologie animale et génétique Chapitres choisis de Développe- The CIG also co–organizes with other biology departments from the Génétique avancée ment Faculty of Biology and Medicine monthly BIG seminars. Conferen- The CIG is committed to the success of its doctoral students. To pro- Biologie et Société Récepteurs nucléaires et régula- ces and symposia are also organized, including the annual Lausanne mote a high level of student achievement, the faculty and adminis- tion génétique Genomics Days and the CIG symposia of which the inaugural sympo- tration take an active role in mentoring and supervising the students. Liliane Michalik sium was in October 2005. With this goal in mind, the CIG has developed an academic mentoring Biologie cellulaire Béatrice Desvergne program. Soon after commencement of his or her studies, each doc- Introduction à l’embryologie Récepteurs nucléaires comme ”In House“ interactions are also particularly precious. At the beginning toral student selects, by mutual agreement of the mentor and mentee, senseurs métaboliques of its existence, in spring 2005, the CIG organized an “Introducing the a faculty member (Professor or Maître d’Enseignement et de Recherche Bernard Thorens Les mécanismes régulateurs des CIG” seminar series, which gave the occasion for all group leaders to (MER)) to be his or her academic mentor. The academic mentor follows Cellule, organe, système voies métaboliques present their work to their new colleagues. Now, seminars and presen- the student’s academic and research progress, and provides advice for Digestion, métabolisme tations among groups working on similar fields are frequent, but it is the duration of the student’s doctoral studies. The academic mentor Liliane Michalik also essential to promote interactions among CIG/Génopode members complements and broadens the learning environment provided by the MASTER COURSES Développement précoce et voies working on different fields. To this aim, a yearly retreat gathering all research mentor. Additionally, by getting to know their mentees well, de signalisation members is organized. academic mentors can promote students’ careers and provide well– Alexandre Reymond, Henrik informed letters of recommendation. Thus, with dual research and aca- Kaessmann Manfredo Quadroni demic mentoring, the CIG ensures a diversity of complementary sup- Last but not least, the CIG is very active in educational activities direc- Evolutionary and comparative Introduction à la protéomique port for better student development and future success. ted at people who are neither biology students nor directly involved genomics in research, but who are interested and concerned by research and its outcomes. These activities take different forms and are addressed to Christian Fankhauser adults or children as well as to biology teachers and schools. Effets de l’environnement sur le développement

48 CIG 2005/2006 Bernard Thorens Keith Harshman (with DAF Métabolisme glucidique et ho- members) méostasie énergétique RNA expression profiling using DNA microarrays (for the SKMB) PhD TUTORIALS MEDICAL STUDIES Winship Herr Reasoning and logic in genetics Bernard Thorens and molecular and cell biology Introduction à l’endocrinologie Métabolisme glucidique Mehdi Tafti, Christian Fankhauser COURSES IN OTHER Circadian clock ORGANIZATIONS

Walter Wahli, Liliane Micha- Alexandre Reymond lik (co–instructor : Nicolas Human genetics Rotman) Bachelor level Nuclear Receptors (for the NCCR University of Geneva Frontiers in Genetics) Functional genomics Bernard Thorens PhD level Energy homeostasis (for the EPFL (Ecole Polytechnique NCCR Frontiers in Genetics) Fédérale de Lausanne)

Laboratory courses Victor Jongeneel SIB–CIG workshops Liliane Michalik and Nouria PhD level Hernandez, co–instructors: UNIL and EPFL (Ecole Erwann Vieu and Nicolas Rot- Polytechnique Fédérale de man (maîtres assistants) Lausanne) Biologie cellulaire et embryologie expérimentale Mehdi Tafti Neurosciences Walter Wahli, Nouria Hernan- University of Geneva dez, Winship Herr, co–instructors : Erwann Vieu and Nicolas Rotman (maîtres assistants) Biologie moléculaire

49 Education | Lectures and courses

PhD Theses Prizes

The following PhD theses have Mathieu Widmer (2006) The following prizes have been been successfully defended at Characterization of GLUT8 and awarded to students at the CIG the CIG : GLUT9, two novel glucose trans- during the years 2005–2006 porter isoforms Group Béatrice Prix d’excellence du jeune Desvergne Sonia Klinger (2006) chercheur, Faculty of Biology and Regulation of mass and function Medicine, University of Lausanne Karim Nadra (2005) of pancreatic b–cells : identifica- (2005) Role of PPARbeta and tion of anti–apoptotic peptides Nicolas Di Poï PPARgamma in mouse placental and role of GLP–1 Group Walter Wahli development Group Walter Wahli Prix de l’Association Vaudoise Alexandra Schumann (2006) des Femmes Diplômées des Early antibiotic administration Raphaël Genolet (2005) Universités (2006) affects the gut barrier function Peroxisome proleferator–acti- Stéphanie Maret and the immune response to oral vated receptor a : Involvement Group Mehdi Tafti antigen in suckling rats in Liver Metabolism and Inflammation Prix de la Société Suisse de Jérôme Feige (2006) Diabète (2006) Integrating receptor interactions David Mutch (2005) Nell Marty and dynamics and interference Exploring the mechanisms Group Bernard Thorens with endocrine disruptors in the regulating nutrient bioavailability mechanisms of action of PPAR and lipid metabolism through a nuclear receptors nutrigenomics approach

Group Bernard Thorens Group LILIANE MICHALIK

Nell Annette Marty (2005) Guillaume Icre (2006) Rôle du transporteur de glucose Role of PPARbeta in keratinocyte GLUT2, dans les mécanismes adhesion and migration during centraux de glucodétection skin wound healing impliqués dans le contrôle de la sécrétion du glucagon et de la prise alimentaire

Mathieu Membrez (2005) Etude de la fonction de GLUT8 sur un modèle de souris knock out

50 CIG 2005/2006 Education | Seminars at the CIG

Seminars

CIG SEMINARS G uy Rousseau Andrew Hattersley BIG SEMINARS INVITATIONS Kateryna Makova function in keratinocyte terminal Université Catholique de Louvain Universities of Exeter & Plymouth BY CIG MEMBERS) Penn State University differenciation Ueli Schibler Louvain, Belgium Exeter & Plymouth, UK University Park, USA University of Geneva One cut transcription fac- Dissecting the beta cell using Edith Heard Strong and weak male mutation Wei Sha Geneva, Switzerland tors control pancreas and liver monogenic diabetes Curie Institute bias at different sites in the pri- Virginia Polytechnic Institute and Circadian time keeping : development Paris, France mate genomes State University the ups and downs of genes, Joanna Wysocka The epigenetic dynamics of Blackburg, USA cells and organs Nicolas Mermod The Rockfeller University X–chromosome inactivation in A nton Nekrutenko Miccroarray data analysis for the University of Lausanne New York, USA the mouse Penn State University genome–wide kinetics of Saccha- Jacques Dubochet Lausanne, Switzerland Reading and writing an epigen- University Park, USA romyces cerevisiae response to University of Lausanne Control of gene expression : from etic mark associated with gene Joan Steitz XLs/ALEX : forced compensatory oxidative stress Lausanne, Switzerland genomics to biotechnology activation : coupling of the cova- Yale University, Howard Hughes evolution of essential signalling CEMOVIS (cryo–electron micros- lent and no–covalent chromatin Medical Institute proteins encoded by overlapping Alea Mills copy of vitreous sections) and R alph Greenspan modification mechanisms New Heaven, USA reading frames Cold Spring Harbor Laboratory CET (computerized electron The Neurosciences Institute Regulatory RNAs : Altering out- New York, USA tomography) : zowards sn stomic San Diego, USA Amanda Fisher comes in gene expression Carley Benton p63 : a new link between cancer, model of the cell From somnolence to alertness : Imperial College London University of Waterloo senescence, and aging dopamine as a modulator of London, UK Robert Tjian Waterloo, Canada Melody Swartz arousal in Drosophila Chromatin profiling of stem cells University of California at Fatty acid transporters and their Hans–Peter Landolt EPFL (Ecole Polytechnique Berkeley regulation in muscle metabolism University of Zurich Fédérale de Lausanne) Jerzy Paszkowski Eileen Furlong Berkeley, USA Zurich, Switzerland Lausanne, Switzerland University of Geneva European Molecular Biology Mechanisms of transcriptional Michael Duszenko Possible contributions of the Lymphangiogenesis and tumor Geneva, Switzerland Laboratory (EMBL) regulation : cross–talk between University of Tuebingen adenosinergic system to trait– invasion : molecular vs. biophysi- Mapping the arabidopsis Heidelberg, Germany activators, co–activators and the Tuebingen, Germany like individual differences in the cal regulators epigenome Transcriptional networks during PIC Prostaglandins and PPARgamma human sleep EEG mesoderm development : dissect- in the protozoan parasite Try- Pierre Magistretti Jonathan Flint ing the logics AD HOC SEMINARS panosoma brucei, the causative Hilary Gates University of Lausanne and EPFL Wellcome Trust Centre for AT THE CIG agent of sleeping sickness University of London (Ecole Polytechnique Fédérale de Human Genetics Michael Hengartner London, UK Lausanne) Oxford, UK University of Zurich Philippe Cettour–Rose David Dombrowicz Complex cross–talk : mutational Lausanne, Switzerland The genetic basis of anxiety Zurich, Switzerland Hôpitaux Universitaires de Institut Pasteur de Lille studies demonstrate how oestro- Neuron–gliaMetabolic coupling : Roads to ruin : apoptotic path- Genève Lille, France gen receptors make the most of relevance for functional brain Gisou Van Der Goot ways in the nematode C. elegans Geneva, Switzerland Skin and mucosal allergic diseas- their differences imaging University of Geneva Reciprocal interactions of thyroid es : immunomodulation and role Geneva, Switzerland Vassily Hatzimanikatis hormones and leptin of Fc receptors (continued on next page) Juerg Tschopp Fundamental cellular processes EPFL (Ecole Polytechnique University of Lausanne revealed by bacterial toxins Fédérale de Lausanne) Manuel Vazquez Carrera Michel Simon Lausanne, Switzerland Lausanne, Switzerland University of Barcelona Université Paul Sabatier The inflammasome : a caspase– Mathematical modeling and Barcelona, Spain Toulouse, France activating complex controlling analysis of complex biological New mechanisms involved in the Peptidylarginine deiminases are innate immunity systems development of insulin resistance new targets for therapy. Their and cardiac hypertrophy

51 Education | Seminars at the CIG (continued)

AD HOC SEMINARS AT THE Coordination of Functionally Profiling the ubiquitin proteome Paris, France Studies of the ANP32 family in Jean Buteau CIG (CONTINUED) Related mRNAs by RNA–binding by quantitative mass spectrom- The level of all ribosome compo- mice (because they have sex) Columbia University proteins etry and identification of protea- nents is subordinated to the con- New York, USA Sophie Van Linthout somal receptor targets trol of RNA polymerase I activity Marie–Agnès Doucey Identification and characteriza- University of Medicine of Berlin Sophie Martin Centre Hospitalier Universitaire tion of CCN3, A NOVel tran- Berlin, Germany Columbia University Marc Fivaz Jan Kopecky Vaudois (CHUV) and University scriptional target of Fox01 in the Are HDL linked to the adiponec- New York, USA Clark Center Academy of Sciences of the of Lausanne beta–cell tin system ? Regulation of actin assembly by Stanford, USA Czech Republic Lausanne, Switzerland formins and microtubules in cell Spatio–temporal regulation of Prague, Czech Republic Profiling signal transduction in Jaya Krishnan Gerd Kullak–Ublick polarization Ras signaling in neurons Induction of metabolic switch by human memory T cells using Pro- Swiss Federal Institute of University Hospital Zurich omega–3 polynsaturated fatty tein Microarrays Technology (ETHZ) Zurich, Switzerland Jennifer Cobb A riella Oppenheim acids in white fat Zurich, Switzerland Genetic regulation of drug and University of Geneva Hebrew University–Hadassah Andrew Hanushevsky HIF–1a in heart disease bile acid transporters : role of Geneva, Switzerland Medical School Zoltan Peterfi Stanford University nuclear receptors ATR kinase and RecQ helicase Jerusalem, Israel University of Szeged Stanford, USA Philippe Besnard orthologs in yeast prevent repli- In vitro assembly of DNA in SV40 Szeged, Hungary Designing high performance data University de Bourgogne Pierre Desreumaux cation fork collapse nanoparticles for gene delivery Hormonal influences on the regu- access systems Dijon, France Hôpital Claude Huriez lation of sleep Do we taste fat ? Lille, France David Kony Matt Webster Ake Bergman PPARgamma, an unknown recep- Swiss Federal Institute of University of Dublin Eric R. Prossnitz Stockholm University Paolo Di Nardo tor involved in gut homeostasis Technology (ETHZ) Dublin, Ireland University of New Mexico Stockholm, Sweden University of Rome Tor Vergata Zurich, Switzerland Regional biases in nucleotide Albuquerque, USA PCB metabolites of concern : Rome, Italy Pipat Nawathean Force field development and substitution patterns during ver- GPR30 : a novel intracellular bioaccumulative and tox- Phenotype determinants of Brandeis University molecular dynamics simulations : tebrate genome evolution transmembrane G protein–cou- ic polychlorobiphenylols and hypertrophic cardiomyopathy Waltham, USA applications to carbohydrates and pled estrogen receptor methylsulfonyl–PCBs Phosphorylation of PERIOD and proteins Adriana Pruzinska Andrzej Stasiak TIMELESS, and Circadian Rhythm University of Bern Adriana Maggi Ruben Nogueiras University of Lausanne Regulation in Drosophila Richard Benton Bern, Switzerland University of Milan University of Santiago of Lausanne, Switzerland The Rockefeller University Biochemical and molecular char- Milan, Italy Compostela. Mechanisms of DNA recombi- Olivier Deloche New York, USA acterization of chlorophyll degra- Novel mechanisms regulat- Compostela, Spain nation, as revealed by electron University of Geneva How flies smell : the molecular dation in higher plants ing estrogen receptor activity Distribution and biological microscopy. Roe of helices and Geneva, Switzerland biology of Drosophila olfaction revealed by in vivo imaging actions of resistin and which rings Translational control of gene Martin Kussmann is the role of visfatin in energy expression : How cells survive a Olivier Pertz Nestlé Research Center Cédric Notredame homeostasis ? Antje Gohla secretory stress ? The Scripps Research Institute Lausanne, Switzerland CNRS Heinrich–Heine–Universität La Jolla, USA OMICS for food – gene, protein Marseille, France Jan H.J. Hoeijmakers Düsseldorf, Germany A ndré Gerber Spatio–temporal control of RhoA and metabolite profiling to find T–Coffee tools : what’s new in Erasmus Medical Center Regulation of cytoskeletal Swiss Federal Institute of activity during cell migration markers and explain benefits the grinder ? Rotterdam, The Netherlands dynamics by Chronophin, a novel Technology (ETHZ) Zurich, DNA damage and the impact on HAD–type phosphatase Switzerland Thibault Mayor Christophe Carles Patrick Reilly cancer and aging, metabolism California Institute of Technology Laboratory of Molecular University of Toronto and the IGF, lifespan regulation Pasadena, USA Biochemistry and Genetics Toronto, Canada

52 CIG 2005/2006 Ferenc Nagy Johan Auwerx Auxin – Cell Polarity and Tissue H alyna Shcherbata function is threatened by envi- Biological Research Center University of Strasbourg Patterning in Plants University of Washington ronmental chemicals that disrupt Szeged, Hungary Strasbourg, France Seattle, USA hormone action What is the function of phyB Turning on energy expenditure Marc Foretz Stem cell division regulated by containing nuclear bodies in light with bile acids or resveratrol University René Descartes microRNAs in Drosophila John Christie induced signaling ? Paris 5, France University of Glasgow C laus Schwechheimer Régulation de l’oxydation des Dorota Retelska Glasgow, UK Stacey Harmer University of Tuebingen acides gras par l’AMPK au cours Copenhagen University Structure and function of the UC Davis Tuebingen, Germany du jeûne dans le foie Copenhagen, Denmark phototropin light–receptor Davis, USA Regulating plant development by Detecting relevant transcription kinases Rhythms and Greens : The plant regulated protein degradation A ndrej Hanzlowsky factor binding sites in promoters clock and its outputs Michigan State University of coexpressed genes Ana M. Soto Jan Lohmann East Lansing, USA Tufts University Toshihiko Yada Max–Planck–Gesellschaft Cloning, expression, purification Frank Buchholz Boston, USA Jichi Medical University, School Tübingen, Germany and characterization of mSNAPc Max Planck Institute for Fetal origins of adult disease : of Medicine Regulatory Networks in Plant Molecular Cell Biology and xenoestrogens and breast cancer Minamikawachi–machi, Japan Stem Cell control Juergen Brosius Genetics Hypothalamic NPY neurons University of Muenster Dresden, Germany integrate metabolic signals to Oliver Mühlemann Muenster, Germany Phenotypic driven mammalian regulate feeding and energy University of Bern The pervasive role of RNA in functional genomics : applications homeostasis Bern, Switzerland genome evolution and cellular to cancer– and stem cell–biology Quality control to gene expres- function Seth Davis sion : mechanisms for recogni- Kateryna Makova Max Planck Institute for Plant tion and elimination of nonsense Bernhard Bettler The Pennsylvania State University Breeding Research mRNA University of Basel University Park, USA Cologne, Germany Basel, Switzerland Male mutation bias and X chro- Molecular detection of the day– Roman Kurek Genetic dissociation of GABA–B mosome inactivation in the age night cycle in Arabidopsis Ambion (Europe) Ltd/Applied receptor functions of genomics Biosystems Sacco De Vries Small Regulatory RNAs and the Richard Benton Laurence Macia Wageningen University Growing RNA World The Rockefeller University Institut Pasteur de Lille Wageningen, The Netherlands New York, USA Lille, France Brassinosteroid signalling in Ara- Monica Gotta How flies smell : the molecular Obésité et immunité : approche bidopsis : the role of co–receptors Swiss Federal Institute of biology of Drosophila olfaction intégrée des interrelations entre Technology (ETHZ) les systèmes neuroendocrinien et Michael Rhodes Zurich, Switzerland Sophie Martin immunitaire Applied Biosystems Asymetric cell division and cell Columbia University Foster City, USA fate specification in C.elegans New York, USA Bernard Weiss Sequencing by oligonucleotide Regulation of actin assembly by University of Rochester ligation and detection (SOLiD) : Jiri Friml formins and microtubules in cell Rochester, USA next generation technology for University of Tübingen polarization Over the course of a lifetime, ultra–high throughput genetic Tübingen, Germany from foetal life to old age, brain and DNA analysis 53 Education | Seminars at the CIG

Lausanne Genomics Towards a human proteome atlas Laurent Duret Julin Maloof Extracting biological meaning Dangerously dancing with cir- Days University Claude–Bernard University of California from high–dimensional “omic” cular logic : Using RNAi to study Panos Deloukas Lyon, France Davis, USA data RNAi Organized within the Sanger Institute Relationships between genome Light and clock regulation of “IIIe cycle Romand en Sciences Cambridge, UK organization and gene expres- plant growth Bing Ren Susan Gasser Biologiques” Human DNA variation – The sion in mammals : Selective Ludwig Institute for Cancer Friedrich Miescher Institute for HapMap project constraints or neutral evolution ? Gregory Wray research (LICR) Biomedical Research (FMI) October 6 and 7, 2005 Duke University San Diego, USA Basel, Switzerland Susan Wessler October 5 and 6, 2006 Durham, USA Mapping the genome’s second 3D “genomics” (organizers : J.Beckmann, University of Georgia Gene expression in primates : code K.Harshman, V.Jongeneel, Athens, USA (organizers : J.Beckmann, evolutionary mechanisms and Ernst Hafen O.Hagenbüchle, C.Fankhauser, Transposable elements : Teaching K.Harshman, V.Jongeneel, functional consequences Inaurgural CIG University of Zurich P.Reymond, L.Keller) old genomes new tricks O.Hagenbüchle, C.Fankhauser, SYMPOSIUM, october 28, Zurich, Switzerland P.Reymond, L.Keller, F.Naef, Robert Williams 2005 Genetics of growth control in Timothy Hughes Marla Sokolowski P.Franken) University of Tennessee Drosophila University of Toronto University of Toronto Memphis, USA (organizers : W. Herr, H. Kaess- Toronto, Canada Mississauga, Canada Michael Lynch Getting inside the brain’s black mann, M. Tafti, B. Thorens) Functional and mechanistic ana- The foraging gene : From nature Indiana University box : a new genomic paradigm in lysis of the mouse transcriptome to molecule and back again Bloomington, USA behavior genetics Denis Duboule The origins of eukaryotic gene University of Geneva Robert Strausberg Justin Borevitz structure Frank Holstege Geneva, Switzerland Venter Institute University of Chicago University Medical Center Chromosome engineering to Rockville, USA Chicago, USA Daniel Tawfik Utrecht, Netherlands study mammalian development Cancer genomics : Integrating Natural variation in light res- Weizmann Institute Understanding mechanisms of basic and clinical research ponse using whole genome tiling Rehovot, Israel eukariotic transcription regula- Nancy Andrews arrays Protein evolution – a reconstruction across the genome Harvard Medical School & Dietmar Schmucker tive approach Howard Hughes Medical Harvard University Greg Gibson David Cox Institute Boston, USA North Carolina State University Trudy Mackay Perlegen InC. Boston, USA Expansion of alternative splicing Raleigh, USA North Carolina State University Mountain View, USA The iron balancing act as an evolutionary strategy to Quantitative transcriptomics : Raleigh, USA Human DNA variation, genetic generate Ig–receptor diversity the nature of gene expression Quantitative genomics and gene- association, and complex traits Ueli Grossniklaus variation tic architecture of complex traits University of Zurich Uri Alon Matthieu Blanchette Zurich, Switzerland Weizmann Institute Detlef Weigel Vincent Colot McGill Center for Bioinformatics Sex, parental conflict, and Rehovot, Israel MPI CNRS Montreal, Canada infanticide Design principles in biology Tübingen, Germany Evry, France In silico reconstruction of an Flowering : mechanisms and nat- Epigenetic variation and its phe- ancestral mammalian genome Gary Ruvkun Mathias Uhlen ural variations notypic impact in Arabidopsis : Harvard Medical School & KTH Biotechnology from (epi)genomics to quantita- John Quackenbush Massachusetts General Hospital Stockholm, Sweden tive genetics Dana–Farber Cancer Institute Boston, USA Boston, USA

54 CIG 2005/2006

Education | CIG retreat Education | The CIG and the public

CIG Retreat The CIG and the public

To promote interactions among its members, the CIG migrates to the A very important aspect of the education activity of the CIG is teach- children! We expect the Passeport Vacances to become one of our Swiss mountains for two to three days at the end of each year. The ing directed at non–biologists. For these activities, we have been very regular activities. groups and facilities present their work in talks and posters. These fortunate to be able to collaborate with the Sciences–Society Interface retreats give opportunities for scientific discussions that can form the (Interface Sciences–Société) and the Center for Continuing Education For adults, we launched with the Center for Continuing Education and basis for interactive projects between groups. Perhaps more impor- (Centre de formation continue) of the University of Lausanne. Our first the Sciences–Society Interface a series of lectures intended for a pub- tantly, they are an occasion for CIG members to interact socially and initiative, spearheaded by maître assistant Laurent Gelman, was a col- lic with little or no knowledge in molecular biology and genetics. The have fun together, simply getting to know each other, and thus con- laboration with the artist Pierre–Philippe Freymond, who installed in lectures addressed basic subjects such as cell division, the genetic code, tribute to the development of a creative and supportive atmosphere the hall of the Génopode his work titled “HeLa”. This installation, which human development, and genetic diseases, and were followed by a at the CIG. had been presented first from March to June 2005 in Geneva during practical course in the Eprouvette, during which the participants iso- the festival “Science et Cité”, is dedicated to Henrietta Lacks, a woman lated DNA. When launching this series, we wondered, would anyone The 2005 and 2006 retreats were in Saas Fee November 23–25, 2005 who died more than 55 years ago of cancer and whose cancer cells are come? Was anyone ready to spend time and money to learn about and December 6–8, 2006. still presently multiplied and used in laboratories worldwide for mo- how dividing cells deal with their genetic information, how DNA codes dern biology research. The display, a sober little white room with a pic- for proteins, how a cell can give rise to all the cell types in an organism, ture of Henrietta Lacks, a catalogue of scientific publications reporting and how minuscule mistakes in the genetic code can have an immense experiments with HeLa cells, and a dish of growing HeLa cells under a influence on an organism? Well, an average of 40 people attended microscope, was inaugurated in the presence of the artist on February each lecture, with an overwhelmingly positive response. Given the 16th 2006. It was a huge success and the work remained in the hall- success of this first “experiment,” we will repeat it, with improve- way of the Génopode until November 2006, time during which it was ments induced by comments of the participants, in particular a greater seen by many visitors in the context of several events, as for example emphasis on connections to disease causes. during a visit by Connaissance 3 (a continuing education program for seniors) participants, during the “Journées de la Recherche en géné- Our ability to organize events for the general public, be it the “Portes tique”, or during the University Open House days. ouvertes” or the “Passeports vacances” depends on the good will and voluntary help of the people working in the CIG and the Génopode : Another venture was the launching in the Summer 2006 of a first par- we thus address many thanks to the participants for imagining activi- ticipation in the program “Passeport Vacances.” This program is orga- ties that they could share with the others, and for communicating their nized by the “Service de la jeunesse et des loisirs” of the Commune de enthusiasm to them. Lausanne and gives children the opportunity to participate to all kinds of different activities, from a visit of a bakery to a try at golf, during school vacations. Starting with a suggestion from Nathalie Clerc, our 4th floor administrative assistant, we added a new possibility to the list of activities, that of spending a morning with DNA experts (Une mati- née avec les experts de l’ADN). Children of two different age groups, from 10 to 12 and from 12 to 15, came to the Dorigny Campus and spent the first hour and a half with the Sciences–Society Interface, iso- lating some DNA in the Eprouvette, their public laboratory! They then came to the CIG for a snack and a visit with a scientist. CIG professors, graduate students, post–docs, and technicians gave some of their time to share with these kids their day–to–day experience in the laboratory. For example, some children looked at a small worm, C.elegans, while some others could get acquainted with the latest microscopy techniques. The kids were fascinated, and the scientists were amazed at the pertinence of some of the questions, especially from the younger

56 CIG 2005/2006 The CIG participated in the following events for the public :

HeLa, installation by Pierre– Lausanne; L’Eprouvette, Interface Philippe Freymond Sciences–Société, University of CIG/Génopode participant : Lausanne L. Gelman November 2006 in collaboration with : A. Kaufman, Interface Sciences– Lecture “continuing educa- Société, University of Lausanne tion for biology teachers” February to November 2006 CIG participant : A. Reymond Journées de la Recherche en in collaboration with : Génétique L’Eprouvette, Interface Sciences– in collaboration with : Société, University of Lausanne; L’Eprouvette, Interface Sciences– Centre suisse de formation conti- Société, University of Lausanne nue des professeurs de l’ensei- May 2006 gnement secondaire (CPS) December 2006 UNIL open house days CIG participants: Other visits to the CIG : M. De Carbonnel, B. Desvergne, M. Hall, N. Hernandez, V. Horn, Connaissance 3 (Université du A. Marques, A. Michels, troisième âge du canton de S. Rodriguez–Jato, L. Rosso, Vaud) J. Thomas, J. Weber, A. Paradis June 2006 Day “osez tous les métiers”, and other visits for groups and Passeport vacances schools CIG participants : G. Boss, N. Clerc, W. Herr, V. Horn, A. Marques, S. Rodri- quez–Jato, L. Rosso, N. Vouilloz in collaboration with : L’Eprouvette, Interface Sciences– Société, University of Lausanne July–August 2006

Lectures “continuing education” CIG participants : N. Hernandez, W. Herr, L. Micha- lik, A. Reymond in collaboration with : Service de formation continue, University of

57 Funding | Acknowledgements

Acknowledgements

Today’s scientific research, particularly in genomics, is a costly enter- EUMORPHIA Human Frontiers Science Johnson & Johnson prise that cannot succeed without significant financial support. The CIG W. Wahli Program Pharmaceuticals is a department of the Faculty of Biology and Medicine (FBM) of the B. Desvergne C. Fankhauser M. Tafti University of Lausanne. As such, the Center is funded by the FBM and the University. In addition, the following organizations have awarded Other international projects Juvenile Diabetes Research Pentapharm research grants to group leaders and personal fellowships to students Foundation International W. Wahli and postdoctoral fellows during 2005–2006 : ENCODE, project of the National B. Thorens Human Genome Research Sanofi Aventis Institute (NHGRI), USA Ludwig Institute for Cancer B. Thorens Research Grants NRP 50 (National Research A. Reymond Research (LICR) To Group Leaders Program 50) Endocrine V. Jongeneel Serono Disruptors : Relevance to Other contributors W. Wahli Swiss National Science Foun- Humans, Animals and National Institutes of Health dation (FNS) Investigator–dri- Ecosystems Cancer Research Institute (NIH), USA Personal fellowships ven research grants W. Wahli V. Jongeneel P. Franken to students and postdocs B. Desvergne N. Hernandez B. Desvergne European Molecular Biology W. Herr European Molecular Biology Organization (EMBO) C. Fankhauser European projects Organization (EMBO) Young Jean–Vincent Chamary (Group Kaessmann) P. Franken Investigator Programme Swiss Institute of Bioinformatics Shweta Tyagi (Group Herr) N. Hernandez SOUTH H. Kaessmann V. Jongeneel W. Herr B. Desvergne Federation of European Biochemical Societies (FEBS) H. Kaessmann Faculty of Biology and Medicine, Telethon Christina Hertel (Group Herr) L. Michalik EMBRACE University of Lausanne, Grant for A. Reymond M. Quadroni ICGRSIB Interdisciplinary research Marie Heim–Vögtlin Fund A. Reymond V. Jongeneel H. Kaessmann Vital-IT Consortium (University of Anne Vassalli (Group Tafti) M. Tafti Lausanne, University of Geneva, B. Thorens EuroDia Fondation Désirée et Niels Yde SIB, Intel Corp., Hewlett Packard) NCCR plant survival W. Wahli V. Jongeneel A. Reymond V. Jongeneel Matthieu De Carbonnel (Group Fankhauser) B. Thorens Swiss National Science Fondation Jérôme LeJeune Corporate contributors Roche Research Foundation Foundation (FNS) targeted EU–STREP grant Molecular A. Reymond Teldja Neige Azzouz (Groupe Hernandez) research grants Evolution of Human Cognition Basilea Pharmaceutica Ltd. Francesca Capostoti (Group Herr) H. Kaessmann Fondation Leenaards W. Wahli Séverine Lorrain (Group Fankhauser) NCCR (National Center of PAF core facility Competence in Research) anEUPloidy Bioresearch Toyobo Biotechnology Foundation Frontiers in Genetics A. Reymond Fondation Novartis W. Wahli Chitose Kami (Group Fankhauser) W. Wahli A. Reymond B. Desvergne HEPADIP GlaxoSmithKline University of Lausanne B. Thorens B. Thorens Germaine de Staëls program B. Desvergne Matthieu De Carbonnel (Group Fankhauser) B. Desvergne

58 CIG 2005/2006 People

The CIG community

The CIG community is composed of more than 170 people representing more than 20 nationalities from 5 continents; during the years 2005 and 2006 there were 14 group leaders or heads of facilities, 3 “maîtres assistants”, 44 postdoctoral fellows, 44 PhD students and 17 master students. The good functioning of the CIG is also critically dependent on the administrative and technical staff working for the different research groups, facilities, central services and administration. Below are listed those individuals who worked at the CIG during 2005-2006:

Agoston Ildiko Stocks and ordering office;IA hmad mtiyaz Group Desvergne; Albarca Monica Group Group Wahli; L’Hôte Philippe Group Hernandez and Group Herr; Liechti Robin Vital-IT; Long Li Vital- Herr; Allenbach Laure Group Fankhauser; AS nghel ilvia Group Wahli; AT zzouz eldja Neige Group IT; Lorrain Séverine Group Fankhauser; Machado Rebelo Marques Ana Group Kaessmann; Maquelin Hernandez; Bady Isabelle* Group Thorens; Barblan Jachen Protein analysis facility – PAF; Barras David* Lionel* Group Kaessmann; Marcillac Fabrice Group Thorens; Maret Stéphanie Group Tafti; Margot Group Wahli; Bauduret Armelle Genotyping; Bedu Elodie Group Desvergne; Ben Mabkhout Elisabeth Delphine Library; Marty Nell Annette Group Thorens; Membrez Mathieu* Group Thorens; Menétrey Washing facility; Berger Marlyne Stocks and ordering office; Bertelli Claire* Group Hernandez; Bozena* Library; Mersch Danielle Group Tafti; Messerli Fabienne Group Herr; Metthez Geneviève Bienvenut Willy* Protein analysis facility – PAF; Bolomey Stéfanie* Animal facility; Bordier Béatrice Group Desvergne; Metref Salima Group Thorens; Michalik Liliane Group Wahli; Michaud Joëlle Group Wahli; Boss Gilles Workshop / Common equipment laboratory; Boyer-Guittaut Michaël* Group Herr; Michels Annemieke Group Hernandez; Montagner Alexandra Group Wahli; Morel Group Hernandez; Brawand David Group Kaessmann and Group Wahli; Brunner Jean-Marc Group Marc Workshop; Moreno Silvia Group Wahli; Moullan Norman Group Wahli; Mounien Lourdes Desvergne; Bueno Manuel DNA array facility – DAF; Calpini Valérie* Group Tafti; Capotosti Francesca Group Thorens; Muller Jocelyne Group Jongeneel and Vital-IT; N adra Karim* Group Desvergne; Nagy Group Herr; C arrard Marianne Genotyping; Carrascosa Coralie Group Herr; Cartier Delestre Muriel Gergely Informatic support; Notari Brigitte Animal facility; Nyffeler Bruno Vital-IT; Pagni Marco Vital- Group Herr; Cerutti Lorenzo Vital-IT; EChaignat velyne Group Reymond; C hamary Jean-Vincent* IT; Paillusson Alexandra DNA array facility – DAF; Paradis Arnaud Cellular imaging facility CIF; Pernet Group Kaessmann; Charrotton Joëlle Animal facility; Chen Pei-Jiun Group Herr; Chrast Jacqueline Nataskha Group Wahli; Peter Corinne Sequencing; Petit Brice Group Tafti; Petit Marlène Group Group Reymond; NClerc athalie Group Fankhauser, Group Hernandez and Group Herr; Colzani Mara Wahli and Group Desvergne; Pfister Corinne Group Tafti; Potrzebowski Lukasz Group Kaessmann; Protein analysis facility – PAF; Constantin Nathalie Group Wahli; C ornu Marion Group Thorens; Potts Alexandra Protein analysis facility – PAF; Poussin Carine Group Thorens; Pradervand Sylvain Cousin Pascal Group Hernandez; ACrevoisier nnick Group Kaessmann, Group Reymond and Group DNA array facility – DAF; Quadroni Manfredo Protein analysis facility – PAF; Ravussin Yann* Group Tafti; CTurie homas Group Franken; Dayer Geneviève* Washing facility; De Carbonnel Matthieu Thorens; RCavy aroline Animal facility; CReina opete Jaime Humberto Group Hernandez; Reymond Group Fankhauser; Debrieux Dimitry Group Fankhauser; Debril Marie-Bernard Group Thorens; Alexandre Group Reymond; Ricci Matteo Group Wahli; R ielle Ludivine Group Jongeneel; Robyr Déglon Agnès* Group Hernandez; Del Rizzo Sébastien* Group Tafti; Delgado Anen* Group Wahli; Anne-Catherine* Group Tafti; Rodriguez-Jato Sara Group Herr; Rossi Daniel* Group Desvergne; Dentan Corinne Central administration; Desvergne Béatrice Group Desvergne; Didelot Gérard Group Rosso Lia Group Kaessmann; RNotman icolas Group Wahli; Rougemont Jacques Vital-IT; Rufener Reymond; Dolci Wanda Group Thorens; Dorsaz Stéphane Group Tafti; Duek Roggli Paula* Group Jézaëlle Animal facility; ASambeat udrey Group Thorens; Sauvain Fabienne DNA array facility – DAF; Fankhauser; Duléry Cécile Group Michalik; Dupanloup Isabelle* Group Kaessmann; CEbring lotaire* SI chepens sabelle Group Fankhauser; Schüpbach Thierry Vital-IT; S chwab Joanna* Group Wahli and Animal facility; El Kochairi Ilhem Group Wahli; E mery Martine Group Thorens; Emmenegger Yann Group Desvergne; Schweizer Fabian Group Fankhauser; S eyer Pascal Group Thorens; S ick Beate* Group Franken; Fabbretti Roberto Vital-IT; Falquet Laurent Vital-IT; Fankhauser Christian Group DNA array facility – DAF; Soyer Jérôme Animal facility; Stevenson Brian Group Jongeneel; Stockinger Fankhauser; Feige Jérôme Group Desvergne; Fiechter Vincent Group Fankhauser; Flegel Volker Vital- Heinz Vital-IT; T afti Mehdi Group Tafti; T allichet Blanc C orinne Group Wahli; Tarussio David Group IT; Flückiger Laurence Group Herr; Franken Paul Group Franken; Freymond Christiane Group Wahli; Thorens; Tavera olmo Beatriz* Group Desvergne; STawffik alma* Group Tafti; Terreau-Haftek Zofia Fu He Group Desvergne; G alaud Delphine* Phenotyping; G elman Laurent* Group Wahli and Group Group Wahli; RTerrier aphael Group Michalik; T homas Jérôme DNA array facility – DAF; Thoppae Desvergne; TGenoud hierry Group Fankhauser; GAerber lan Group Desvergne; AGnecchi lain* Animal Gnanasekaran DNA array facility – DAF and Protein analysis facility – PAF; T horens Bernard Group facility; Goldstein Darlene DNA array facility – DAF; Gouait Patrick Animal facility; SGuernier ophie Thorens; Thottathil Oommen Sajit Group Desvergne; Trevisan Martine Group Fankhauser; Tyagi Group Herr; Gurcel Laure Group Tafti; G yger Joël Group Thorens; Hagenbüchle Otto DNA array facility Shweta Group Herr; Varnat Frédéric Group Desvergne; Vassalli Anne Group Tafti; Vaucher Angélique – DAF; H all Diana Group Thorens; Hall Matthew Group Desvergne; CHänggeli orinne Informatic Group Wahli; Vienne Julie Group Tafti; Vieu Erwann Group Hernandez; Vinckenbosch Nicolas Group support; Harewood Louise Group Reymond; Harshman Keith DNA array facility – DAF; HS asan ubah Kaessmann; Vouilloz Nicole Central administration; Wahli Walter Group Wahli; Waridel Patrice Protein Group Tafti; H assler Vanessa Group Wahli; Hausherr Katharina Genotyping; Henrichsen Charlotte analysis facility – PAF; Wawrzyniak Marta Group Michalik; Weber Johann DNA array facility – DAF; Group Reymond; Hernandez Nouria Group Hernandez; H err Winship Group Herr; CHertel hristina Weier Manuela Group Kaessmann; Wertenberg Marianne Group Wahli; Wicker Sophie DNA array Group Herr; Hoffmann-Denarié Claudia Group Thorens; H orn Virginie Group Herr; Hornitschek facility – DAF; Wierzbicki Bartosz Apprentice; Willemin Gilles* Group Thorens; Winkler Christine* Patricia Group Fankhauser; HCowald édric Group Reymond; HCrobova rausaz Henrieta* Group Wahli Group Thorens; Wyser Céline Apprentice; Zahn-Zabal Monique Group Jongeneel; Zimmermann and Group Hernandez; GIcre uillaume* Group Wahli; I glésias José Group Wahli; I ngman Maxwell Cynthia Washing facility Group Kaessmann; Ioannidis Vassilios Vital-IT; ICseli hristian Group Jongeneel; Jeronimo Virginie Group Wahli; Jimenez Maria Group Thorens; Jongeneel Victor Group Jongeneel and Vital-IT; Joye *left the CIG Elisabeth Phenotyping and Group Desvergne; Junod Fabienne Animal facility; Kaessmann Henrik Group Kaessmann; Kami Chitose Group Fankhauser; Klinger Sonia Group Thorens; Kostadinova Radina Group Wahli; Krauskopf Alexandra Group Wahli; Kuznetsov Dimitry Group Jongeneel; Lathion Caroline* Group Wahli; Laverrière–Schultz Monique* Group Thorens; Leuenberger Nicolas