Chair
Professor Douglas Epstein, University of Pennsylvania, USA
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Professor Douglas Epstein, University of Pennsylvania, USA
Professor Douglas Epstein, University of Pennsylvania, USA
"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."
Remote control of Shh gene expression in the limb bud
Professor Robert Hill, MRC IGMM, University of Edinburgh, Scotland
Abstract
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.
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Professor Robert Hill, MRC IGMM, University of Edinburgh, Scotland
Professor Robert Hill, MRC IGMM, University of Edinburgh, Scotland
"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."
Charting the genome regulatory architecture with transposons
Dr Francois Spitz, European Molecular Biology Laboratory, Germany
Abstract
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.
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Dr Francois Spitz, European Molecular Biology Laboratory, Germany
Dr Francois Spitz, European Molecular Biology Laboratory, Germany
"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."
High Throughput Enhancer Assessment In Vivo
De Len Pennacchio, Lawrence Berkeley National Laboratory, USA
Abstract
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.
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De Len Pennacchio, Lawrence Berkeley National Laboratory, USA
De Len Pennacchio, Lawrence Berkeley National Laboratory, USA
"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."
Transcriptional enhancers in development and variation of the human face
Professor Joanna Wysocka, Stanford School of Medicine, USA
Abstract
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.
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Professor Joanna Wysocka, Stanford School of Medicine, USA
Professor Joanna Wysocka, Stanford School of Medicine, USA
"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."