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Human DNA methylomes at base resolution show widespread epigenomic differences
Open accessAbstract
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.
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“In most somatic tissues, the majority (>80%) of CpGs in the genome are methylated, with the exception of CGIs, and other gene regulatory sequences that show reduced 5mC levels (3).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [3]
In the citing paper
“In PMD associated tissues such cultured fibroblasts, genes located in PMDs are both lowly expressed and methylated (3).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [3]
In the citing paper
“Human embryonic stem cells (hESC) and mammalian brain tissues contain abundant non-CG methylation (5mCH, where H equals A, C or T) although the underlying three-base DNA sequence context (5mCAG vs. 5mCAC, respectively) is distinct (3, 13).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [3]
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Metadata
- Authors
- Lister, R., Pelizzola, M., Dowen, R. H., Hawkins, R. D., Hon, G., Tonti-Filippini, J., Nery, J. R., Lee, L., Ye, Z., Ngo, Q.-M., Edsall, L., Antosiewicz-Bourget, J., Stewart, R., Ruotti, V., Millar, A. H., Thomson, J. A., Ren, B., & Ecker, J. R.
- Affiliations
- Salk Institute for Biological Studies (US)
- Ludwig Cancer Research (BE)
- Morgridge Institute for Research (US)
- The University of Western Australia (AU)
- University of Wisconsin–Madison (US)
- Corresponding author
- Ecker, Joseph R.
- ORCID
- Venue
- Nature
- Published
- 2009-10-14
- Volume
- 462
- Issue
- 7271
- Pages
- 315-322
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2857523
- OpenAlex
- W2059099579
- Cited by
- 4,673
- References
- 50
- Citations by year
- 2026: 132 · 2025: 178 · 2024: 214 · 2023: 207 · 2022: 237 · 2021: 251 · 2020: 232 · 2019: 256 · 2018: 273 · 2017: 282 · 2016: 304 · 2015: 356 · 2014: 350 · 2013: 374 · 2012: 373
- FWCI
- 136.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Funders
- California Institute for Regenerative Medicine
- National Institutes of Health
- Australian Research Council (DP0771156, CE0561495)
- National Human Genome Research Institute (R01HG003523)
- National Institute of Environmental Health Sciences (U01ES017166, U01 1U01ES017166-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- DNA methylation, methylome, cytosine methylation, non-CG methylation, human embryonic stem cells, fetal fibroblasts, differentially methylated regions, pluripotency, cell differentiation, induced pluripotent stem cells, histone modifications, protein-DNA interactions, gene expression regulation, epigenome, gene body methylation, enhancer methylation
- MeSH terms
- Cell Line, DNA, DNA-Binding Proteins, Humans, Cluster Analysis, Genome, DNA Methylation, Epigenesis, Genetic, Embryonic Stem Cells
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