Human DNA methylomes at base resolution show widespread epigenomic differences.
DNA cytosine methylation is a central epigenetic modification that has essential roles in cellular processes including genome regulation, development and disease. Here we present the first genome-wide, single-base-resolution maps of methylated cytosines in a mammalian genome, from both human embryonic stem cells and fetal fibroblasts, along with comparative analysis of messenger RNA and small RNA components of the transcriptome, several histone modifications, and sites of DNA-protein interaction for several key regulatory factors. Widespread differences were identified in the composition and patterning of cytosine methylation between the two genomes. Nearly one-quarter of all methylation identified in embryonic stem cells was in a non-CG context, suggesting that embryonic stem cells may use different methylation mechanisms to affect gene regulation. Methylation in non-CG contexts showed enrichment in gene bodies and depletion in protein binding sites and enhancers. Non-CG methylation disappeared upon induced differentiation of the embryonic stem cells, and was restored in induced pluripotent stem cells. We identified hundreds of differentially methylated regions proximal to genes involved in pluripotency and differentiation, and widespread reduced methylation levels in fibroblasts associated with lower transcriptional activity. These reference epigenomes provide a foundation for future studies exploring this key epigenetic modification in human disease and development.
Lister
Ryan
R
Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Pelizzola
Mattia
M
Dowen
Robert H
RH
Hawkins
R David
RD
Hon
Gary
G
Tonti-Filippini
Julian
J
Nery
Joseph R
JR
Lee
Leonard
L
Ye
Zhen
Z
Ngo
Que-Minh
QM
Edsall
Lee
L
Antosiewicz-Bourget
Jessica
J
Stewart
Ron
R
Ruotti
Victor
V
Millar
A Harvey
AH
Thomson
James A
JA
Ren
Bing
B
Ecker
Joseph R
JR
D002460:Cell Line; D016000:Cluster Analysis; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism; D044127:Epigenesis, Genetic; D016678:Genome / Q000235:genetics*; D006801:Humans
D004268:DNA-Binding Proteins; D004247:DNA