Distinct DNA methylation patterns characterize differentiated human embryonic stem cells and developing human fetal liver
- Alayne L. Brunner1,5,
- David S. Johnson1,5,6,
- Si Wan Kim1,5,
- Anton Valouev2,
- Timothy E. Reddy3,
- Norma F. Neff1,
- Elizabeth Anton1,
- Catherine Medina1,
- Loan Nguyen1,
- Eric Chiao1,
- Chuba B. Oyolu1,
- Gary P. Schroth4,
- Devin M. Absher3,
- Julie C. Baker1,8 and
- Richard M. Myers1,7,8
- 1 Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
- 2 Department of Pathology, Stanford, California 94305, USA;
- 3 HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA;
- 4 Illumina, Inc., San Diego, California 92121, USA
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↵5 These authors contributed equally to this work.
Abstract
To investigate the role of DNA methylation during human development, we developed Methyl-seq, a method that assays DNA methylation at more than 90,000 regions throughout the genome. Performing Methyl-seq on human embryonic stem cells (hESCs), their derivatives, and human tissues allowed us to identify several trends during hESC and in vivo liver differentiation. First, differentiation results in DNA methylation changes at a minimal number of assayed regions, both in vitro and in vivo (2%–11%). Second, in vitro hESC differentiation is characterized by both de novo methylation and demethylation, whereas in vivo fetal liver development is characterized predominantly by demethylation. Third, hESC differentiation is uniquely characterized by methylation changes specifically at H3K27me3-occupied regions, bivalent domains, and low density CpG promoters (LCPs), suggesting that these regions are more likely to be involved in transcriptional regulation during hESC differentiation. Although both H3K27me3-occupied domains and LCPs are also regions of high variability in DNA methylation state during human liver development, these regions become highly unmethylated, which is a distinct trend from that observed in hESCs. Taken together, our results indicate that hESC differentiation has a unique DNA methylation signature that may not be indicative of in vivo differentiation.
Footnotes
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↵6 Present addresses: Gene Security Network, Inc., Redwood City, CA 94063, USA;
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↵7 HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
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↵8 Corresponding authors.
E-mail rmyers{at}hudsonalpha.org; fax (256) 327-0978.
E-mail jbaker{at}stanford.edu: fax (650) 725-1534.
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[Supplemental material is available online at www.genome.org. Raw Methyl-seq sequence data are available from NCBI's Short Read Archive (http://www.ncbi.nlm.nih.gov/Traces/sra/sra.cgi) (accession no. SRA008154). Processed Methyl-seq data are available for download and visualization at http://genome-test.cse.ucsc.edu/cgi-bin/hgTrackUi?db=hg18&g=wgEncodeHudsonalphaMethylSeq. Gene expression data can be downloaded from NCBI's GEO (http://www.ncbi.nlm.nih.gov/geo/) (accession no. GSE14966). Additional information and files can be found at http://myers.hudsonalpha.org.]
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Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.088773.108.
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- Received December 1, 2008.
- Accepted March 6, 2009.
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Freely available online through the Genome Research Open Access option.
- Copyright © 2009 by Cold Spring Harbor Laboratory Press
