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Expression driven in the developing mouse by the wild-type cat-derived sonic hedgehog ZRS limb enhancer (Image courtesy of Dr Laura Lettice)
Scientific discussion meeting organised by Professor Wendy Bickmore and Professor Veronica van Heyningen FRS
The correct regulation of gene expression underpins normal development and differentiation, and is frequently perturbed in disease. Whilst events controlling transcription around gene promoters are well understood, how far-distant enhancers direct spatial and temporalcontrol of transcription is less clear. Our aim is to integrate experimental and computational approaches, in multiple model systems, to define the mechanisms of enhancer action. This meeting will bring together experts in the field to discuss their research and ideas and key challenges for the future.
Biographies of the organisers and speakers are available below and you can also download the programme (PDF). Recorded audio of the presentations will be available on this page after the event and papers will be published in a future issue of Philosophical Transactions B.
This event is intended for researchers in relevant fields and is free to attend. There are a limited number of places and registration is essential. An optional lunch is offered and should be booked during registration (all major credit cards accepted).
Participants are also encouraged to attend the related satellite meeting Regulation of gene expression from a distance: exploring mechanisms which immediately follows this event.
Enquiries: Contact the events team
Professor Douglas Epstein, University of Pennsylvania, USAChair
Douglas Epstein is an Associate Professor in the Department of Genetics at the Perelman School of Medicine, University of Pennsylvania. He received his PhD under the supervision of Dr Philippe Gros at McGill University working on the genetic basis of neural tube defects in mice. For his postdoctoral training, he first worked in Andy McMahon’s lab at Harvard and identified members of the mouse Hedgehog gene family, and then moved to Alex Joyner’s lab at the Skirball Institute in New York where he began his studies on the regulation of Sonic hedgehog (Shh) transcription. Current research in his lab at UPenn focuses on the temporal and spatial dynamics of Shh expression and function during vertebrate central nervous system development, including the elucidation of pathogenic mechanisms underlying congenital brain anomalies caused by Shh misregulation.
Professor Robert Hill, MRC IGMM, University of Edinburgh, ScotlandRemote control of Shh gene expression in the limb bud
Multi-species conserved non-coding elements occur in the vertebrate genome and are clustered in the vicinity of developmentally regulated genes. Many act as cis-regulators of transcription and may reside at long distances from the genes they regulate. The relationship of conserved sequence to encoded regulatory information and indeed, the mechanism by which these contribute to long-range transcriptional regulation is not well understood. The ZRS, a highly conserved cis-regulator, is a paradigm for long-range gene regulation acting over ~1Mb to control spatiotemporal expression of Shh in the limb bud. In addition mutations in this regulator account for a number of limb abnormalities which include polydactyly, tibial hypoplasia and syndactyly. We describe the modular nature of this developmental regulator and show that a number of activities are encoded by this enhancer. Restriction of the expression pattern in the limb can, at least in part, be attributed to distinct binding sites in highly conserved domains that lie in the ZRS. Members of two groups of ETS transcription factors mediate a differential effect on Shh expression, defining the parameters of the expression pattern. Occupancy at multiple GABP/ETS1 sites regulates the position of the ZPA boundary, whereas ETV4/ETV5 binding restricts expression outside the ZPA. In addition analyses over longer sequence stretches dissect the ZRS into two distinct activities; one that regulates spatiotemporal activity and one that controls the long-range activity. Spatiotemporal activity is encoded within an element which functions efficiently only from a close range; whereas, long range activity is encoded by a second element which transmits the spatiotemporal activity over a large genomic distance. These two encoded regulatory activities integrate to control the number of digits and morphologically, ensure a stable limb phenotype based on a pattern of five digits.
Professor Hill received his PhD (in 1974) in biochemistry from the University of Tennessee at the Oak Ridge National Laboratories. His research interests throughout his career have focused around mechanisms responsible for organogenesis during embryonic development. His first postdoc was at Roswell Park Memorial Institute in New York and secondly at the MRC (now called the Human Genetics Unit) where he spent the majority of his research career. Limb development interests stem initially from work looking at the control of homeobox containing gene expression in the limb. Since then he has been interested in a common limb disorder, preaxial polydactyly (hand and foot deformities including extra digits), establishing disease mechanisms that disrupt the normal limb development.
Dr Francois Spitz, European Molecular Biology Laboratory, GermanyCharting the genome regulatory architecture with transposons
Vertebrate genomes are characterized by the presence of cis-regulatory elements located at great distances from the genes they control. Genomic rearrangements found in humans suggest that the specific organization of large loci is not random, but contributes importantly to implement the specific activities of these remote enhancers. To determine the organization of the mammalian genome and identify elements and genomic parameters that define enhancer regulatory activities, we have developed an in vivo approach, building on the controlled mobilization of a Sleeping Beauty transposon to distribute a regulatory sensor throughout the mouse genome. Analysis of a large genome-wide collection of insertions revealed principles of the genome regulatory architecture. Furthermore, the properties of Sleeping Beauty, in combination with in vivo chromosomal engineering, allows investigation of the fine-scale structure of loci of interests, shedding light on how remote enhancers may control target gene expression.
After graduating from the Ecole Polytechnique, François Spitz did his PhD at University Pierre-et-Marie-Curie (Paris), working on the transcriptional control of muscle-fiber subtype-specific gene expression. He joined the group of Denis Duboule (University of Geneva) in 1998 where he identified and studied the long-range regulatory enhancers that control the expression of the posterior Hoxd genes in the developing limb buds. Since 2006, he has been a group leader in the Developmental Biology Unit at the EMBL Heidelberg. His group aims to decipher the mechanisms that control and establish specific functional interactions between genes and remote cis-regulatory elements. They have notably developed advanced in vivo chromosomal engineering strategies to identify the principles of the complex regulatory architecture of the mammalian genomes, and to understand how changes in genome structure could lead to developmental defects and diseases in humans.
De Len Pennacchio, Lawrence Berkeley National Laboratory, USAHigh Throughput Enhancer Assessment In Vivo
The paucity of a defined collection of mammalian transcriptional enhancers has largely precluded both our ability to develop computational methods for predicting additional tissue-specific enhancers in the human genome and to assess such sequences for their role in human disease. In ongoing studies, we are leveraging extreme evolutionary sequence conservation as well as next generation ChIP-Sequencing to identify putative gene regulatory elements and are characterizing their in vivo enhancer activity in a transgenic mouse assay. To date we have tested over 2000 such sequences in animals, and observed that >1000 function reproducibly as tissue-specific enhancers of gene expression. As a community resource, we have established a database to visualize and query the activity of these enhancer sequences (http://enhancer.lbl.gov/) and continue to generate additional in vivo enhancer data for >300 sequences per year. In recent studies directly from human tissues, we show that the conservation of enhancers across mammals varies widely depending on the specific tissue of examination. In particular, enhancers of the nervous system have high levels of evolutionary constraint while enhancers of the heart are largely not conserved. These findings highlight the importance of enhancer identification directly from human tissues for certain organs and hence disease states. In addition, this growing set of enhancers with in vivo-defined activities provides a molecular toolbox that can be used to experimentally target gene expression to organs and tissues in animals and constitutes a starting point for studying the role of regulatory elements in human disease.
Len Pennacchio is a Senior Staff Scientist in the Genomics Division at Lawrence Berkeley National Laboratory (LBNL) and Deputy Director of the DOE Joint Genome Institute. Dr Pennacchio has an extensive background in mammalian genetics and genomics as well as with DNA sequencing technologies and their application to address outstanding issues in both the medical and energy sectors. He received his PhD in 1998 from the Department of Genetics at Stanford University and performed his postdoctoral work with Eddy Rubin as an Alexander Hollaender Distinguished Fellow at LBNL. He has authored over 100 peer-reviewed publications and in 2007 received the Presidential Early Career Award for Scientists and Engineers (PECASE) from the White House for his contributions to the Human Genome Project and understanding mammalian gene regulation in vivo.
Professor Joanna Wysocka, Stanford School of Medicine, USATranscriptional enhancers in development and variation of the human face
The face is at the center of our identity: it is the feature that best distinguishes an individual, while also connecting each of us to our broader ethnic ancestry and to the genetic inheritance from our parents, often evident in familial resemblances. And yet we know very little about the genetic basis of human facial variation. Nonetheless, a growing number of reports documents a link between enhancer mutations and complex human diseases. Moreover, evidence from model organisms begins to emerge that genetic variation in cis-regulatory elements underlies much of morphological evolution and diversity. Although human craniofacial development is extremely complex, the central bauplan of facial morphology is established early in embryogenesis by the neural crest cells and their derivatives. We recently developed an in vitro model of human neural crest formation and used it to epigenomically annotate enhancer repertoire if this unique cell type. I will discuss our hypothesis that allelic sequence variants of neural crest enhancers regulate normal-range variation of craniofacial features and confer susceptibility for malformations.
Joanna Wysocka, PhD, is an Assistant Professor in the Department of Chemical and Systems Biology and the Department of Developmental Biology at Stanford University. She has done her graduate work at the Cold Spring Harbor Laboratory with Dr Winship Herr and postdoctoral training at the Rockefeller University with Dr David Allis. In the fall of 2006, Dr Wysocka established her independent research group at Stanford University, where her research is focused on understanding chromatin-mediated mechanisms that regulate self-renewal and differentiation with particular interest in the molecular basis of developmental plasticity. Dr Wysocka received numerous awards for her research, including the Searle Scholar Award, Baxter Award, Terman Fellow Award, California Institute for Regenerative Medicine New Faculty Award, W.M. Keck Foundation Distinguished Young Scholar Award and 2010 International Society for Stem Cell Research Outstanding Young Investigator Award.
Professor Martha Bulyk, Brigham & Women’s Hospital and Harvard Medical School, USAChair
Dr. Bulyk received dual undergraduate degrees in Biology and in Mathematics from MIT in 1993. She received her PhD in Biophysics in 2001 from Harvard University, where she worked in Dr George Church’s group and pursued research on transcription factors and their DNA binding sites. Shortly thereafter, she began as an Assistant Professor at Harvard. Currently she is Associate Professor in the Division of Genetics in the Department of Medicine at Brigham & Women's Hospital and Harvard Medical School. She also holds a secondary appointment in the Department of Pathology at Brigham & Women's Hospital, is an Associate Member of the Broad Institute of MIT and Harvard, and is an Associate Member of the Dana Farber Cancer Institute’s Center for Cancer Systems Biology.
In 2005 Dr. Bulyk was named one of the TR35, MIT Technology Review’s annual competition to select the top 35 young innovators under the age of 35, and in 2007 she was named in Genome Technology’s annual selection of “Tomorrow’s PIs”. Dr Bulyk has published over 60 papers, and her group is currently focused on studies of transcription factors and DNA regulatory elements, using a variety of experimental and computational approaches, including new technologies they have developed.
Professor Douglas Higgs FRS, Weatherall Institute of Molecular Medicine, University of Oxford, UKA novel approach for characterising chromosomal interactions throughout the genome
Cis-acting elements (promoters, enhancers, silencers, locus control regions, boundary elements) can often be identified via their conserved, non-coding DNA sequences. In addition, when active, they may have characteristic chromatin signatures and are bound by transcription factors and polymerase II. Such features can now be identified across the entire genome by chromatin immunoprecipitation (using ChIP on chip and ChIPseq). However, cis-elements (e.g. promoters and enhancers) may be located 100s or even 1000s kb apart and therefore it is often not clear which regulatory sequence (e.g.enhancer) interacts with which promoter or additional regulatory element. The chromosome conformation capture (3C) technique was designed to analyse physical interactions between specific, previously characterised, widely separated DNA elements and it has been shown that such interactions are an inherent feature of their function. We have adapted the 3C protocol and developed a method which is capable of identifying all DNA elements interacting with a selected sequence (e.g. promoter) without any prior knowledge of these elements. To validate this approach, we have initially applied this method to the human globin locus in which the interacting cis-elements have been previously characterised in detail. Using this modified chromosome conformation capture technique we can simultaneously identify the known regulatory elements with high resolution and have shown that they occur in a tissue-specific manner. The method can be applied to the entire genome and is easily analysed using tiled micro-arrays or by high-throughput sequencing which provides additional information on the nature of individual interactions.
Douglas Higgs (FRS) qualified in Medicine at King’s College Hospital Medical School in 1974 and trained as a haematologist. He joined the MRC Molecular Haematology Unit (Oxford) in 1977 and is currently Professor of Molecular Haematology at the University of Oxford and Director of the MRC Molecular Haematology Unit. The current interests of the Unit are (i) to understand the processes by which stem cells undergo lineage commitment in haematopoiesis; (ii) to understand how genes are activated and repressed during normal haematopoiesis; (iii) to study the human genetic diseases affecting these processes. The main interest of Professor Higgs’s laboratory have been to understand how the globin genes are regulated during haematopoiesis from their natural chromosomal environment in the telomeric region of 16p13.3. His group has characterised the terminal 2 Mb of chromosome 16 and concentrated on understanding how globin gene expression is influenced by the transcriptional programme and epigenetic modifications of this region (e.g. chromatin structure, histone acetylation, methylation, timing of replication, nuclear positioning). This work contributes to our understanding of the normal process of blood formation and provides an unusually well characterised model for understanding the mechanisms underlying mammalian gene regulation. He has previously supervised 30 graduate students, 8 Biochemistry Part 2 projects, and numerous laboratory visitors. In addition Professor Higgs has trained over 30 post doctoral Fellows and Clinical Training Fellows. He regularly examines PhD and DPhil theses (approximately 2-3 per year for the past 25 years).
Professor Emmanouil Dermitzakis, University of Geneva, SwitzerlandRegulatory genomics in human populations
Molecular phenotypes are important phenotypes that informs about genetic and environmental effects on cellular state. The elucidation of the genetics of gene expression and other cellular phenotypes are highly informative of the impact of genetic variants in the cell and the subsequent consequences in the organism. In this talk I will discuss recent advances in three key areas of the analysis of the genomics of gene expression and cellular phenotypes in human populations and multiple tissues and how this assists in the interpretation of regulatory networks and human disease variants. I will also discuss how the recent advances in next generation sequencing and functional genomics are bringing closer our hopes for personalized medicine.
Emmanouil Dermitzakis is currently a Louis-Jeantet Professor of Genetics in the Department of Genetic Medicine and Development of the University of Geneva Medical School. He is a member of the executive board of the Institute of Genetics and Genomics in Geneva (iGE3) since 2011 and is also an affiliated Faculty member at the Biomedical Research Foundation of the Academy of Athens in Greece. He obtained his BSc in 1995 and MSc in 1997 in Biology from the University of Crete (Greece) (with Prof. Lefteri Zouros) and his PhD in 2001 from the Pennsylvania State University in the US (with Prof. Andrew Clark), studying the evolutionary biology and population genetics of regulatory DNA in mammals and Drosophila. His post-doctoral work was at the University of Geneva Medical School, focusing on comparative genome analysis and the functional characterization of conserved non-genic elements. He previously was an Investigator and Senior Investigator at the Wellcome Trust Sanger Institute since April 2004. His current research focuses on the genetic basis of regulatory variation and gene expression variation in the human genome, the processes that govern non-coding DNA evolution. He has authored and co-authored more than 100 papers in peer-reviewed journals and many of them in journals such as Nature, Science and Nature Genetics. His papers have cited more than 14000 times and his H-index is 40. His research is supported by the Louis-Jeantet Foundation, the Wellcome Trust, the Swiss National Science Foundation, the European Commission, the Juvenile Diabetes Foundation and the US National Institutes of Health (NIH). He is also the recipient of a European Research Council (ERC) grant. He has been invited to give talks and keynote lectures in most of the prestigious genetics meeting and is the organizer of multiple training courses including the Wellcome Trust HapMap course and founder and organizer of the Leena Peltonen School of Human Genomics. He has served as an analysis co-chair in the pilot phase of the ENCODE (ENCyclopedia Of Dna Elements) consortium and member of the analysis group of the Mouse Genome Sequencing Consortium and the International HapMap project. He had a leading analysis role in the extension of the HapMap (aka HapMap3 project) and is a member of the analysis group of the 1000 genomes project. He has served in the Board of Reviewing Editors of Science (2006-2011), and he is a Senior Editor in PLoS Genetics.
Professor Matthew Freedman, Harvard Medical School, USAConnecting non-protein coding risk loci with their target genes
A fundamental goal of human genetics is to uncover the relationship between genotype and phenotype. To date, genome wide association studies (GWAS) have identified thousands of alleles associated with hundreds of traits. In stark contrast to Mendelian disorders, the majority of trait-associated loci are located outside of known protein coding areas. This observation poses the next set of challenges for follow-up and fine mapping of trait-associated alleles: (i) what gene is the allele is acting through? and (ii) what is the actual trait causing polymorphism(s)?. For Mendelian disorders, answers to both of these questions are usually revealed through sequencing the coding regions of candidate genes. The genetic code provides the necessary insight and ability to readily interpret DNA sequence changes and how they impact amino acids. Since there is no analogous code for non-protein coding regions, identifying the genes and causal allele(s) underlying complex diseases presents key challenges. The focus of our group is to develop strategies to address these topics.
Biography not yet available
Professor John Stamatoyannopoulos, University of Washington, USAFunctional connectivity between human regulatory regions
The human genome is densely populated with enhancers and other distal regulatory elements, yet little is currently known about their functional scope. Reverse genetics in an isogenic setting coupled with epigenome profiling offers a powerful paradigm for elucidating the functional network of any cis-regulatory region, and is now enabled through the application of designer nucleases. Applying this approach to the β-globin Locus Control Region (LCR) on Chr11 reveals this classical regulatory element to be functionally connected to over 1,000 predominantly erythroid-specific promoters and distal regulatory elements genome-wide. Genome-scale analysis of chromatin contacts reveals that the affected elements interact both with the LCR and with one another, and share common patterns of transcription factor occupancy. The results reveal unexpected and potent functional synchrony among large numbers of regulatory DNA regions distributed across the human genome.
John Stamatoyannopoulos, M.D., is an Associate Professor of Genome Sciences and Medicine at the University of Washington School of Medicine. He graduated from Stanford University in 1990 with degrees in Biology, Symbolic Systems, and Classics, and received an M.D. in 1995 from the University of Washington. He completed residency in Internal Medicine at Brigham and Women's Hospital, Harvard Medical School, and was a fellow in Oncology and Hematology at Dana Farber Cancer Institute and the Massachusetts General Hospital. Dr. Stamatoyannopoulos joined the Departments of Genome Sciences and Medicine (Oncology) at the University of Washington in 2005. Dr. Stamatoyannopoulos' lab focuses on understanding the regulatory circuitry of the human genome and those of major model organisms, and the genetic basis of common human diseases and traits.
Professor Patricia Simpson FRS, University of Cambridge, UKChair
Pat Simpson obtained her PhD from the Université Pierre et Marie Curie (Paris VI) in 1976 on the genetic mechanisms underlying pattern formation in Drosophila. After working for two years at the University of California, Irvine, she spent 25 years as a scientist for the French scientific civil service (CNRS) in various laboratories in Paris and Strasbourg. Her work focussed on the role of Notch signalling in determining differences between identical cells (lateral signalling) during embryonic development, using the spaced bristle array of Drosophila as a model system. Her team moved to Cambridge in 2000 to work on the role of evolution of cis-regulatory sequences in generating diversity in animal morphology, using the achaete-scute genes in Diptera as a model.
Professor David Kingsley, HHMI and Stanford University School of Medicine, USAMapping the genetic and genomic basis of evolutionary change in vertebrates
The relative contribution of coding and regulatory mutations to adaptive evolution has been difficult to assess, particularly in non-model organisms subject to a full range of fitness constraints in the wild. Recent improvements in genetic and genomic methods are making it possible to map key regions controlling adaptive traits in threespine stickleback fish, and to identify the type of mutations that underlie interesting evolutionary differences seen in nature. Patterns learned from initial case histories can now be extended to the entire genome, using large-scale genotyping and sequencing of many different populations that have evolved similar traits in response to similar environments. Recent studies show that regulatory changes make up the predominant category of mutation that underlies repeated adaptive evolution in threespine sticklebacks. Remarkably similar patterns are seen in genome-wide studies of adaptive loci in both sticklebacks and humans, showing the importance of regulatory differences for a detailed understanding of the molecular basis of evolutionary change in vertebrates.
Dr Kingsley received his undergraduate degree in Biology from Yale University in 1981, and his PhD in Biology from MIT in 1986. He trained in somatic cell genetics as a graduate student with Monty Krieger, and in molecular mouse genetics as a Lucille P. Markey postdoctoral fellow with Neal Copeland and Nancy Jenkins. As a Professor and Howard Hughes investigator in the Department of Developmental Biology at Stanford, Dr Kingsley has identified the molecular basis of several classical mouse skeletal mutations, dissected complex regulatory elements in developmental control genes, and pioneered the genetic and genomic analysis of vertebrate evolution using natural populations of threespine stickleback fish. He has received the Belknap Prize and Henry Chittendon Award from Yale University, the Conklin Medal for distinguished research in Developmental Biology, and is a member of the American Academy of Arts and Sciences and the National Academy of Sciences, USA.
Dr Ivan Ovcharenko, National Institutes of Health, USAComputational identification and sequence analysis of enhancers
Transcriptional activation is commonly assumed to rely on ubiquitous promoters establishing the basal level of expression and interacting with tissue-specific enhancers responsible for temporal and cellular expression fine-tuning. We previously developed a computational approach to model the motif structure of tissue-specific enhancers and demonstrated its accuracy in predicting heart and hindbrain enhancers, for which 60% and 90% of predictions, respectively, have been validated in vivo. To address the lack of tissue-specificity in promoters, we applied the developed motif analysis approach to the sequence of promoters of tissue-specific genes. Unexpectedly, a strong tissue-specificity signal has been observed in promoters of genes expressed in some tissues, including heart and liver. To validate the identified signal as a general mark of tissue-specificity, we used it to predict distant tissue-specific enhancers. These predictions were notably overrepresented in loci of concordantly expressed genes (6-fold enrichment in liver predictions, for example; p-value < 1e-20). When tested in in vivo enhancer assays, 60% of the liver predictions have been confirmed as positive enhancers. Our results suggest dichotomy in promoter use in different regulatory programs.
Ivan Ovcharenko is an Investigator at the Computational Biology Branch of NCBI, NLM at the National Institutes of Health (NIH) and Adjunct Professor at Boston University. He holds a PhD degree in Physics and Mathematics from the Novosibirsk State University, Russia. Prior to joining NIH, Dr Ovcharenko was a Scientist at the Lawrence Livermore National Laboratory (LLN) and Lawrence Berkeley National Laboratory (LBNL). He is an editorial member of Bioinformatics and BMC Bionformatics. The research of the Ovcharenko research group focuses on deciphering semantics and studying evolution of the gene regulatory code in eukaryotes.
Professor Denis Duboule, University of Geneva and EPFL Lausanne, SwitzerlandLarge scale switch in Hox genes regulation during limb development
The emergence and evolution of limbs was an essential step in the success of vertebrates. Amongst the key players, Hoxd genes are coordinately regulated during the development of both the proximal (arm and forearm) and distal (digits) regions. In both contexts, these genes help organize growth and patterns. We examined the associated long-range transcriptional regulation by probing their 3D organization and chromatin status in developing limbs, at both early and late stages, combined with scanning deletion approaches in vivo. During digit development, we show that the active part of the gene cluster contacts several regulatory islands, located within the centromeric gene desert, which all contribute either quantitatively or qualitatively to Hox gene transcription in future digits. This novel type of ‘regulatory archipelago’ may underlie both the great morphological flexibility in the shape and number of digits as well as their resilience to drastic variations. In contrast, during arm and forearm development, a partially overlapping set of genes is regulated via the telomeric gene desert, as determined again by conformation capture, chromatin landscapes and transgenic as well as genetic approaches. Therefore, completely different regulatory strategies have evolved to build these two parts of our developing appendages. The evolutionary relevance of this two-steps strategy will be discussed as well as the switch between these various regulatory modalities.
Denis Duboule earned his PhD in Biology in 1984. He is currently Professor of Developmental genetics and genomics at the Federal Institute of Technology in Lausanne and Chairman of the department of Genetics and Evolution of the University of Geneva, Switzerland. Since 2001, he is also the director of the Swiss national research centre ‘Frontiers in Genetics’. Duboule has a longstanding interest in the function and regulation of Hox genes, a family of genes responsible for the organization and evolution of animal body plans. These genes have been a paradigm to understand embryonic patterning, in developmental, evolutionary and pathological contexts. He is an elected member of several academies and has received many awards, amongst which the Louis-Jeantet Prize for Medicine in 1998.
Professor Wendy Bickmore, University of Edinburgh, UKThe spatial organisation of the enhancers – is what you ‘C’ what you see?
Our understanding of chromatin states beyond the level of the nucleosome is rudimentary. Until quite recently there has been little exploration of how higher-order chromatin structure might contribute to the regulation of gene expression, but it is hard to envisage how distant enhancers can regulate expression from their target genes located many hundreds of thousands of base pairs away, without invoking chromosome folding. Using specific developmentally regulated loci in the mouse I will discuss how chromatin compaction and chromatin looping can act to regulate the spatial and temporal activation of genes during mouse development. I will compare different molecular and cytological methods that can probe higher order chromatin structure and will discuss whether these methods both point to a consensus view of enhancer function or not. I will also present evidence for a new histone modification that marks some active enhancers in embryonic stem cells.
Wendy Bickmore is the Head of the Chromosomes and Gene Expression Section at the MRC Human Genetics Unit, MRC IGMM at the University of Edinburgh. Her scientific work is based on the principle being that genes do not function in isolation from their chromosomal and nuclear context. She has pioneered research into the spatial and temporal organisation of the human and mouse genomes, and the implications of this for gene regulation and genome function. Her experimental approaches combine cell biology with genomics, genetics and biochemistry. Wendy is an EMBO member, and a Fellow of both the Royal Society of Edinburgh and the Academy of Medical Sciences.
Dr Edith Heard, Institut Curie, FranceChair
Edith Heard was trained as a geneticist at Cambridge University and carried out her PhD at the ICRF (London), working on gene amplification in cancer cells. During her post doc at the Pasteur Institute in Paris, she began her work on X-chromosome inactivation and the functional and evolutionary dissection of the X-inactivation center. Since 2001 she has led the Mammalian Developmental Epigenetics team at the Curie Institute. She is also head of the Genetics and Developmental Biology Department. Her laboratory works on various aspects of X-chromosome inactivation and its epigenetic regulation, with a particular interest in the role of non-coding RNAs, nuclear organization and chromatin changes in coordinating this chromosome-wide silencing process during early mammalian development.
Professor Wouter de Laat, Hubrecht Institute & Utrecht Medical Center, The NetherlandsTranscription regulation in the 3D nucleus
Developmental gene regulation in mammals is often controlled by remote regulatory DNA sequences. ChIP-seq and other functional genomics profiles indicate the genome is full of potential regulatory DNA sequences. In order to understand how they are wired to genes, detailed 3D genome maps are required. I will present our work that aims to develop improved versions of 3C technology in order to understand how gene expression is controlled in the 3D nucleus.
Wouter de Laat studied biology at the Utrecht University Utrecht and did his PhD with Professor Jan Hoeijmakers at the Erasmus University Rotterdam, investigating the molecular mechanism of nucleotide excision repair. As a postdoc, he joined the group of Professor Frank Grosveld to work on beta-globin gene activation. In 2000 he received a career grant (Vidi) to work on long-range gene activation. His group used 3C technology, and later developed 4C technology, to demonstrate chromatin loops between genes and enhancers and to uncover long-range DNA contacts within and between chromosomes. In 2008 he received an ERC Young Investigator Grant. In September 2008 de Laat moved his group to the Hubrecht Institute, where he continued his work on genome structure and function. In January 2009 he was appointed Professor in Biomedical Genomics at the University Medical Center Utrecht.
Dr Gioacchino Natoli, European Institute of Oncology, ItalyDeciphering cis-regulatory control of inflammatory cells
Cell identity is determined by a complex and dynamic interplay between cell-intrinsic, lineage-restricted developmental pathways on the one hand, and cell-extrinsic micro-environmental signals on the other. In this context, macrophages represent a paradigmatic cell population whose functional specialization in vivo reflects the impact of the local microenvironment on the intrinsic differentiation program, leading to a variety of specialized macrophage types in different tissues and conditions. Players and mechanisms controlling macrophage plasticity and at the same time enforcing macrophage identity will be discussed.
Gioacchino Natoli is a group leader at the Department of Experimental Oncology of the European Institute of Oncology (IEO) in Milan. Dr Natoli obtained his MD degree and specialist training in Internal Medicine from the University of Rome. He then moved to basic research and joined the group of Michael Karin at UCSD for a postdoctoral training in 1998, working on NF-kB regulation of inflammation. In 2000 he moved to Switzerland (Institute for Research in Biomedicine) to run an independent research group and in 2005 he joined the IEO. The main research interest of Dr Natoli in recent years has been the regulation of inflammation and specifically chromatin-mediated control of inflammatory responses. Work form Natoli's group has allowed identifying mechanisms controlling complex temporal patterns of inflammatory gene expression. More recent work has focused on the role of chromatin modifiers and particularly histone demethylases in inflammation.
Dr Bing Ren, Ludwig Institute for Cancer Research UCSD, USATopological domains: identification and functional implications in gene regulation
The structural organization of the genome has a fundamental role in its function. The transcription regulatory process, for example, involves higher order chromatin structures, where transcriptional activation is frequently mediated through long range looping interactions between promoters and enhancers and accompanied by dynamic chromatin movement in the nucleus. As such, knowledge of the higher order chromatin structure is essential for a full understanding of transcriptional control and other nuclear processes. Recently, we have investigated the 3D organization of the human and mouse genomes with the Hi-C technique, and found that these genomes are partitioned into large, megabase-sized local chromatin interaction domains, which we term “topological domains”. Here, I will discuss the functional implications of structural feature in gene regulation, and present evidence that topological domains may be involved in long-range control of gene expression by distal enhancer sequences.
Dr Ren is currently Member of the Ludwig Institute for Cancer Research (LICR) and Professor of Cellular and Molecular Medicine at the University of California, San Diego School of Medicine. He leads the San Diego Epigenome Center, one of four NIH-sponsored Reference Epigenome Mapping Centers as part of the Roadmap Epigenomics project. He obtained his PhD from Harvard University in 1998, where he studied mechanisms of transcriptional repression under the guidance of Dr Tom Maniatis. From 1998 to 2001, he continued to research mechanisms of gene regulation and genomics as a postdoctoral fellow in Dr Richard Young’s laboratory at Whitehead Institute. During this period he developed the ChIP-chip analysis method. At UCSD and LICR, Dr Ren continued to use genomic approaches investigate the gene regulatory networks and epigenetic mechanisms in eukaryotic cells. Research accomplishments from the laboratory include development of high throughput method for mapping transcription factor binding sites in the human genome, comprehensive mapping of promoters, enhancers, and insulator elements in the human genome, and characterization of the epigenomic landscapes in pluripotent and lineage-committed human cells.
Panel discussion 25 May
Public lecture 29 May
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