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Human Epigenome Project

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 Year URL

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Human Epigenome Project

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  1. Human Epigenome Project Stephan Beck Wellcome Trust Sanger Institute

  2. Human Epigenome Project 1. Lessons learnt 2. Towards an integrated (epi)genetic approach to common disease

  3. ‘Epigenome’ Projects Year URL • ______________________________________________________________________ • Human Epigenome Project (HEP) 2000 www.epigenome.org • Epigenome Network of Excellence 2004 www.epigenome-noe.net • Center for Epigenetics of Common 2004 www.genome.gov/12511135#3 • Human Disease • National Methylome 21 (NAME21) 2005 www.faculty.iu-bremen.de • Epigenetic Treatment of Neoplastic 2005 www.epitron.eu • Disease (EPITRON) • Highthroughput Epigenetic Regulatory 2005 www.heroic-ip.eu • Organisation In Chromatin (HEROIC) • Epigenetic Control of the Mammalian 2006 http://www.gen-au.at • Genome (GEN-AU) • Advances with Human Embryonic Stem 2006 www.estools.eu • Cells (ESTOOLS) • Alliance for the Human Epigenome 2008 new NIH Roadmap Initiative • and Disease (AHEAD)

  4. www.epigenome.org

  5. Study Design • Distribution • Specificity • Function • Stability • Conservation

  6. www.epigenome.org

  7. Eckhardt et al. 2006 Nature Genet 38:1379-85 Methylation Profiles CpG density

  8. 5’-UTR; mean: 0.363 intragenic; mean: 0.753 Distribution Rakyan et al. 2004 PLoS Biol 2(12):e405 Eckhardt et al. 2006 Nature Genet 38:1379-85

  9. Specificity Eckhardt et al. 2006 Nature Genet 38:1379-85

  10. http://expression.gnf.org <-------- Lung -------> <------ Prostate -----> <-------- Liver -------> Function Rakyan et al. 2004 PLoS Biol 2(12):e405 Eckhardt et al. 2006 Nature Genet 38:1379-85

  11. Promoter Methylation Eckhardt et al. 2006 Nature Genet 38:1379-85

  12. Stability Eckhardt et al. 2006 Nature Genet 38:1379-85

  13. Conservation Eckhardt et al. 2006 Nature Genet 38:1379-85

  14. Differentially Methylated Regions Eckhardt et al. 2006 Nature Genet 38:1379-85

  15. 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

  16. MeDIP Input Methylation enriched Methylation depleted Genome-wide assay using MeDIP Weber et al. 2005 Nat Genet. 37:853-862

  17. Rakyan et al., in preparation Epigenome profiling • 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 r = 0.97 (binned); r = 0.84 (unbinned)

  18. Towards an integrated (epi)genetic approach to common disease “reverse phenotyping”

  19. phen MVPs X X BisSeq DMRmap HapMap tag SNPs WGAmap X X X DeepSeq phen SNPs (eHapMap) Integrated (epi)genetic approach Genome candidate ‘hepitype’

  20. (Epi)genotyping

  21. (Epi)genotyping

  22. (Epi)genotyping Murrell et al. 2005 Hum Mol. Genet. 14:R3-10

  23. new TS gene exp profiling CLL Christoph Plass eHapMap snp profiling (epi)genotyping analysis met profiling Cell, June issue 2007 MS Stephen Sawcer George Ebers ND new susceptibility locus eHapMap snp profiling (epi)genotyping analysis met profiling Ann Neurol 61, 2007 ? IBD Stefan Schreiber exp profiling ND snp profiling (epi)genotyping analysis met profiling T1D David Leslie exp profiling ? ND snp profiling (epi)genotyping analysis met profiling ? LOI CRC/BC Adele Murrell ND ND ND (epi)genotyping analysis ND Examples in progress done

  24. HEP Acknowledgements 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 BerlinJan 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 Collaborators European Bioinformatics Institute, UK Paul Flicek Stefan Gräf Cambridge Research Institute, UK Nathalie ThorneAdele Murrell Ohio State University, US Christoph Plass International MS Genetics Consortium Stephen Sawcer George Ebers Institute of Cell & Molecular Science, UK Huriya Beyan David Leslie Kiel University, DE Robert Häsler Philip Rosenstiel Stefan Schreiber

  25. HEP Statistics Eckhardt et al. 2006 Nature Genet 38:1379-85

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