Stem Cell Characteristics

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Nature 462, 315-322 (19 November 2009) | doi:10.1038/nature08514; Received 19 June 2009; Accepted 21 September 2009; Published online 14 October 2009


Human DNA methylomes at base resolution show widespread epigenomic differences
Ryan Lister1,9, Mattia Pelizzola1,9, Robert H. Dowen1, R. David Hawkins2, Gary Hon2, Julian Tonti-Filippini4, Joseph R. Nery1, Leonard Lee2, Zhen Ye2, Que-Minh Ngo2, Lee Edsall2, Jessica Antosiewicz-Bourget5,6, Ron Stewart5,6, Victor Ruotti5,6, A. Harvey Millar4, James A. Thomson5,6,7,8, Bing Ren2,3 & Joseph R. Ecker1

Correspondence to: Joseph R. Ecker1 Correspondence and requests for materials should be addressed to J.R.E. (Email: ecker@salk.edu).


Abstract 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.

1.Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA
2.Ludwig Institute for Cancer Research,
3.Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California 92093, USA
4.ARC Centre of Excellence in Plant Energy Biology, The University of Western Australia, Crawley, Western Australia 6009, Australia
5.Morgridge Institute for Research, Madison, Wisconsin 53707, USA
6.Genome Center of Wisconsin, Madison, Wisconsin 53706, USA
7.Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin 53715, USA
8.Department of Anatomy, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
9.These authors contributed equally to this work.