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Epigenetic reprogramming in mammalian development
If you have a question about this talk, please contact Hannah Critchlow.
This talk is part of the Cambridge Clinical Neuroscience and Mental Health Symposium, 29th – 30th September 2009 at West Road Concert Hall. This event is free to attend for cambridge neuroscientists although registration is required. To register, and for further information, please visit: http://www.neuroscience.cam.ac.uk/cnmhs/
Abstract: We study epigenetic mechanisms of gene regulation and their impact in mammalian development. Long noncoding RNAs play important roles in imprinting, including potentially in regulating gene expression and physiology of networks of imprinted genes. We have found that the imprinted long noncoding RNA H19 is the most conserved regulatory noncoding RNA in mammalian evolution, and may have a function in fine tuning growth. The imprinted long noncoding RNA Kcnq1ot1, by contrast, targets epigenetic gene silencing in cis to a genomic region which is 1 Megabase in size. We have found that this RNA is localised to the nucleus where it ‘coats’ the chromosome region it inactivates.
Epigenetic reprogramming occurs in early embryos and in primordial germ cells, and is important for imprinting, pluripotency of the embryonic and germ cell genome, and for the erasure of epimutations. We are carrying out genome-wide screens for DNA methylation, and comparing several pluripotent and more differentiated cell types, in order to understand the extent of methylation reprogramming and what sequences are regulated by it. We have recently carried out genome-wide Bisulphite-Seq in primordial germ cells, which has revealed the extent of reprogramming on an unprecedented scale.
We have also begun to test the hypothesis that epigenetic regulation is important for lineage commitment and its stability. We identified a trophoblast transcription factor, Elf5, that is methylated and repressed in ES cells, but unmethylated and expressed in TS cells. Expression of this transcription factor sustains a positive feedback loop between key trophoblast fate determinants, and is thus necessary for trophoblast commitment. By contrast, epigenetic silencing of this trophoblast determinant in the epiblast lineage disrupts the feedback loop so that trophoblast cell fate is aborted should it initially take place. This type of epigenetically regulated feedback loop appears to ensure initial plasticity followed by canalization of lineage fate.
Smits et al Nature Genetics 40, 971-976 (2008) Ng et al Nature Cell Biology 10, 1280-1290 (2008) Ponting et al Cell 136, 629-641 (2009)
Biography: Wolf Reik is Associate Director of Research and Head of the Laboratory of Developmental Genetics and Imprinting at the Babraham Institute in Cambridge. After receiving his MD from the Universities of Freiburg and Hamburg in Germany, he went on to study for his postgraduate degree with Rudolf Jaenisch (on retroviruses, epigenetics, DNA methylation) before undertaking postdoctoral work with Azim Surani (on genomic imprinting) in Cambridge as an EMBO Fellow. He was a Fellow of the Lister Institute of Preventive Medicine, and headed the Programme of Developmental Genetics at the Babraham Institute before taking up his current post as Associate Director of the Institute. He has a joint appointment on the board of management of the Centre for Trophoblast Research at the University of Cambridge, and as Professor of Epigenetics in the Department of Physiology, Development, and Neuroscience.
Wolf Reik’s research interests are in genomic imprinting and in epigenetic mechanisms of gene regulation in early embryos, germ cells, and stem cells, and in particular in the role of epigenetic reprogramming in developmental plasticity. He has published more than 140 research papers, and received a number of prizes and distinctions for his work, including the Wellcome Prize of Physiology. He is an elected member of EMBO and a Fellow of the Academy of Medical Sciences. He has served on several national and international academic boards and is currently a member of the Cancer Research UK Science Funding Committee. He is a member of editorial boards of several academic journals and of Faculty 1000. He also sits on the Executive Board of The Epigenome EU Network of Excellence, is a consultant to CellCentric, Cambridge, and on the Scientific Advisory Board, Center for Genomic Regulation, Barcelona.
This talk is part of the Clinical Neuroscience and Mental Health Symposium series.
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