Human Epigenome Project Stephan Beck Wellcome Trust Sanger Institute
Human Epigenome Project 1. Lessons learnt 2. Towards an integrated (epi)genetic approach to common disease
‘Epigenome’ Projects YearURL ______________________________________________________________________ Human Epigenome Project (HEP) Epigenome Network of Excellence Center for Epigenetics of Common Human Disease National Methylome 21 (NAME21) Epigenetic Treatment of Neoplastic Disease (EPITRON) Highthroughput Epigenetic Regulatory Organisation In Chromatin (HEROIC) Epigenetic Control of the Mammalian Genome (GEN-AU) Advances with Human Embryonic Stem Cells (ESTOOLS) Alliance for the Human Epigenome 2008 new NIH Roadmap Initiative and Disease (AHEAD)
Study Design Distribution Specificity Function Stability Conservation
Methylation Profiles CpG density Eckhardt et al Nature Genet 38:
5’-UTR; mean: intragenic; mean: Distribution Rakyan et al PLoS Biol 2(12):e405 Eckhardt et al Nature Genet 38:
Specificity Eckhardt et al Nature Genet 38:
Function Rakyan et al PLoS Biol 2(12):e405 Eckhardt et al Nature Genet 38:
Promoter Methylation Eckhardt et al Nature Genet 38:
Stability Eckhardt et al Nature Genet 38:
Conservation Eckhardt et al Nature Genet 38:
Differentially Methylated Regions Eckhardt et al Nature Genet 38:
Conclusions Methylation profiles are stable, specific and to a large extend binary Methylation at promoters (TSS) correlates with gene expression Majority of methylation profiles are conserved and DMRs enriched at ECRs Need for faster and genome-wide assay
Weber et al Nat Genet. 37: Genome-wide assay using MeDIP MeDIP Input Methylation enriched Methylation depleted
Designed custom ‘epigenome’ arrays (Nimblegen) for human and mouse Generated DNA methylation profiles and DMRs for 16 human and 6 mouse tissues/cell lines First human DNA methylation data to be included in ENSEMBL Epigenome profiling Rakyan et al., in preparation r = 0.97 (binned); r = 0.84 (unbinned)
Towards an integrated (epi)genetic approach to common disease “reverse phenotyping”
Genome tag SNPs HapMap WGAmap DeepSeq phen SNPs (eHapMap) BisSeq DMRmap phen MVPs candidate ‘hepitype’ Integrated (epi)genetic approach XXXXX
(Epi)genotyping
Murrell et al Hum Mol. Genet. 14:R3-10
Examples in progressdone MS Stephen Sawcer George Ebers eHapMapsnp profiling (epi)genotypinganalysis ND met profiling new susceptibility locus IBD Stefan Schreiber NDsnp profiling (epi)genotypinganalysis exp profiling met profiling ? T1D David Leslie NDsnp profiling (epi)genotypinganalysis exp profiling met profiling ? ND (epi)genotypinganalysis ND LOI CRC/BC Adele Murrell ? Ann Neurol 61, 2007 CLL Christoph Plass eHapMapsnp profiling (epi)genotypinganalysis exp profiling met profiling new TS gene Cell, June issue 2007
Human Epigenome Consortium Wellcome Trust Sanger Institute, UK Dan Andrews David Jackson John Attwood Jennifer Liddle John Burton David Niblett Liselotte Bäckdahl Karen Novik Antony Cox Roger Pettett Rob Davies Vardhman Rakyan Thomas Down Jane Rogers Roger Horton Eleni Tomazou Kevin Howe Tony West Epigenomics-AG, DE Kurt Berlin Jan Kunde Matthias Burger Christoph König Rene Cortese Jörn Lewin Florian Eckhardt Alexander Olek Carolina Häflinger Thomas Otto Thomas Hildmann Stefanie Seemann Christinan Thompson Centre National de Genotypage, FR Ivo GutJörg Tost Judith Fischer HEP Acknowledgements Collaborators European Bioinformatics Institute, UK Paul FlicekStefan Gräf Cambridge Research Institute, UK Nathalie Thorne Adele Murrell Ohio State University, US Christoph Plass International MS Genetics Consortium Stephen SawcerGeorge Ebers Institute of Cell & Molecular Science, UK Huriya BeyanDavid Leslie Kiel University, DE Robert HäslerPhilip Rosenstiel Stefan Schreiber
HEP Statistics Eckhardt et al Nature Genet 38: