Louise Laurent1,2,8, Eleanor Wong3,4,8, Guoliang Li5,9, Tien Huynh6,9, Aristotelis Tsirigos6,9, Chin Thing Ong3, Hwee Meng Low3, Ken Wing Kin Sung5,7, Isidore Rigoutsos6,10, Jeanne Loring2,10 and Chia-Lin Wei3,4,10
-Author Affiliations
1UCSD Medical Center, Department of Reproductive Medicine, San Diego, California 92103, USA;
2Center for Regenerative Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA;
3Genome Technology & Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore;
4Department of Biological Sciences, National University of Singapore, Singapore 119077, Singapore;
5Computational & Mathematical Biology, Genome Institute of Singapore, Singapore 138672, Singapore;
6Bioinformatics & Pattern Discovery Group, IBM Thomas J. Watson Research Center, Yorktown Heights, New York 10598, USA;
7Department of Computer Science, School of Computing, National University of Singapore, Singapore 119077, Singapore
↵8 These authors contributed equally to this work.
↵9 These authors contributed equally to this work.
Abstract
DNA methylation is a critical epigenetic regulator in mammalian development. Here, we present a whole-genome comparative view of DNA methylation using bisulfite sequencing of three cultured cell types representing progressive stages of differentiation: human embryonic stem cells (hESCs), a fibroblastic differentiated derivative of the hESCs, and neonatal fibroblasts. As a reference, we compared our maps with a methylome map of a fully differentiated adult cell type, mature peripheral blood mononuclear cells (monocytes). We observed many notable common and cell-type-specific features among all cell types. Promoter hypomethylation (both CG and CA) and higher levels of gene body methylation were positively correlated with transcription in all cell types. Exons were more highly methylated than introns, and sharp transitions of methylation occurred at exon–intron boundaries, suggesting a role for differential methylation in transcript splicing. Developmental stage was reflected in both the level of global methylation and extent of non-CpG methylation, with hESC highest, fibroblasts intermediate, and monocytes lowest. Differentiation-associated differential methylation profiles were observed for developmentally regulated genes, including the HOX clusters, other homeobox transcription factors, and pluripotence-associated genes such as POU5F1, TCF3, and KLF4. Our results highlight the value of high-resolution methylation maps, in conjunction with other systems-level analyses, for investigation of previously undetectable developmental regulatory mechanisms.
Footnotes
↵10 Corresponding authors.
E-mail rigoutso@us.ibm.com.
E-mail jloring@scripps.edu.
E-mail weicl@gis.a-star.edu.sg.
[Supplemental material is available online at http://www.genome.org. Sequence data from this study have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) under accession no. GSE19418.]
Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.101907.109.
Received October 14, 2009.
Accepted December 15, 2009.
Copyright © 2010 by Cold Spring Harbor Laboratory Press
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