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 YearURL ______________________________________________________________________ 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 Neoplastic2005 www.epitron.eu Disease (EPITRON) Highthroughput Epigenetic Regulatory2005 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 Stem2006 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

7. www.epigenome.org

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

9. 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

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

11. http://expression.gnf.org Function Rakyan et al. 2004 PLoS Biol 2(12):e405 Eckhardt et al. 2006 Nature Genet 38:1379-85

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

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

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

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

16. 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

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

18.  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)

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

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

21. (Epi)genotyping

23. Murrell et al. 2005 Hum Mol. Genet. 14:R3-10

24. 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

25. 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

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