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Genome-scale DNA methylation maps of pluripotent and differentiated cells
Open accessAbstract
DNA methylation is essential for normal development and has been implicated in many pathologies including cancer. Our knowledge about the genome-wide distribution of DNA methylation, how it changes during cellular differentiation and how it relates to histone methylation and other chromatin modifications in mammals remains limited. Here we report the generation and analysis of genome-scale DNA methylation profiles at nucleotide resolution in mammalian cells. Using high-throughput reduced representation bisulphite sequencing and single-molecule-based sequencing, we generated DNA methylation maps covering most CpG islands, and a representative sampling of conserved non-coding elements, transposons and other genomic features, for mouse embryonic stem cells, embryonic-stem-cell-derived and primary neural cells, and eight other primary tissues. Several key findings emerge from the data. First, DNA methylation patterns are better correlated with histone methylation patterns than with the underlying genome sequence context. Second, methylation of CpGs are dynamic epigenetic marks that undergo extensive changes during cellular differentiation, particularly in regulatory regions outside of core promoters. Third, analysis of embryonic-stem-cell-derived and primary cells reveals that 'weak' CpG islands associated with a specific set of developmentally regulated genes undergo aberrant hypermethylation during extended proliferation in vitro, in a pattern reminiscent of that reported in some primary tumours. More generally, the results establish reduced representation bisulphite sequencing as a powerful technology for epigenetic profiling of cell populations relevant to developmental biology, cancer and regenerative medicine.
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“They provide better genomic coverage than 450K array, and can assess the genetic variants and allele-specific methylation beyond the preselected microarray probes.”
From Integrative Analysis of Multi-omics Data for Discovery and Functional Studies of Complex Human Diseases (2016) · cites this paper as Meissner et al., 2008
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“DNA methylation is thought to be involved in disease pathology through its influence on gene expression and cellular function5,6.”
From Methylome-wide change associated with response to electroconvulsive therapy in depressed patients (2021) · cites this paper as [6]
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Epigenetic inheritance and the missing heritability
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“It has been shown that during early mitotic divisions of a mammalian embryo, daughter cells derived from the zygote have a globally hypomethylated genome [50] and a transcriptionally active chromatin due to histone H4 acetylation [51].”
BackgroundThe DNA Methylome of Human Peripheral Blood Mononuclear Cells
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Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming
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DNA methylation: TET proteins—guardians of CpG islands?
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Astrocytic abnormalities and global DNA methylation patterns in depression and suicide
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Genetics and epigenetics: stability and plasticity during cellular differentiation
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Brain function and chromatin plasticity
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Metadata
- Authors
- Meissner, A., Mikkelsen, T. S., Gu, H., Wernig, M., Hanna, J., Sivachenko, A., Zhang, X., Bernstein, B. E., Nusbaum, C., Jaffe, D. B., Gnirke, A., Jaenisch, R., & Lander, E. S.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Broad Institute (US)
- Corresponding author
- Jaenisch, Rudolf
- Lander, Eric S.
- ORCID
- Venue
- Nature
- Published
- 2008-07-06
- Volume
- 454
- Issue
- 7205
- Pages
- 766-770
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2896277
- OpenAlex
- W2161224111
- Cited by
- 2,536
- References
- 30
- Citations by year
- 2026: 40 · 2025: 53 · 2024: 74 · 2023: 81 · 2022: 73 · 2021: 124 · 2020: 91 · 2019: 110 · 2018: 102 · 2017: 141 · 2016: 138 · 2015: 192 · 2014: 194 · 2013: 218 · 2012: 230
- FWCI
- 91.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Broad Institute
- National Human Genome Research Institute (R01HG004401, U54HG003067)
- 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 › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- DNA methylation, embryonic stem cells, cell differentiation, CpG islands, histone methylation, epigenetic profiling, neural cells, hypermethylation, transposable elements, conserved non-coding elements, mice, cancer epigenetics, regenerative medicine
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Fibroblasts, Histones, Male, Neurons, Genome, Conserved Sequence, CpG Islands, DNA Methylation, Genomics, Pluripotent Stem Cells, Mice, Embryonic Stem Cells
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