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______________________________________________________________________

• 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)

www.epigenome.org

Study Design

Distribution

Specificity

Function

Stability

Conservation

www.epigenome.org

Methylation Profiles

CpG density

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

5’-UTR; mean: 0.363intragenic; mean: 0.753

Distribution

Rakyan et al. 2004 PLoS Biol 2(12):e405Eckhardt et al. 2006 Nature Genet 38:1379-85

Specificity

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

<-------- Lung -------> <-------- Liver -------><------ Prostate ----->

http://expression.gnf.org

Function

Rakyan et al. 2004 PLoS Biol 2(12):e405Eckhardt et al. 2006 Nature Genet 38:1379-85

Promoter Methylation

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

Stability

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

Conservation

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

Differentially Methylated Regions

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

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. 2005 Nat Genet. 37:853-862

Genome-wide assay using MeDIP

MeDIPInput

Methylationenriched

Methylationdepleted

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

XX XX XX

XXXX

(Epi)genotyping

(Epi)genotyping

(Epi)genotyping

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

Examples in progress done

MSStephen Sawcer

George EberseHapMap snp profiling (epi)genotyping analysis

ND

met profiling

newsusceptibility

locus

IBDStefan Schreiber

ND snp profiling (epi)genotyping analysis

exp profiling

met profiling

?

T1DDavid Leslie

ND snp profiling (epi)genotyping analysis

exp profiling

met profiling

?

ND ND (epi)genotyping analysis

ND

ND

LOI CRC/BCAdele Murrell

?

Ann Neurol 61, 2007

CLLChristoph Plass

eHapMap snp profiling (epi)genotyping analysis

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 Gut Jörg Tost Judith Fischer

HEP

AcknowledgementsCollaborators

European Bioinformatics Institute, UK Paul Flicek Stefan Gräf

Cambridge Research Institute, UK Nathalie Thorne Adele 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

HEP Statistics

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