Upload
isaac-newman
View
223
Download
0
Tags:
Embed Size (px)
Citation preview
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