Cited by 2,536Epigenetics and DNA MethylationGenomics and Chromatin DynamicsPluripotent Stem Cells Research

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Genome-scale DNA methylation maps of pluripotent and differentiated cells

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Meissner, Alexander, Mikkelsen, Tarjei S., Gu, Hongcang, Wernig, Marius, Hanna, Jacob, Sivachenko, Andrey, Zhang, Xiaolan, Bernstein, Bradley E., Nusbaum, Chad, Jaffe, David B., Gnirke, Andreas, Jaenisch, Rudolf, Lander, Eric S.·2008·Nature

DOI 10.1038/nature07107PMC PMC2896277

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Abstract

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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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: Meissner, Alexander
Mikkelsen, Tarjei S.
Gu, Hongcang
Wernig, Marius
Hanna, Jacob
Sivachenko, Andrey
Zhang, Xiaolan
Bernstein, Bradley E.
Nusbaum, Chad
Jaffe, David B.
Gnirke, Andreas
Jaenisch, Rudolf
Lander, Eric S.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2008-07-06
Volume: 454
Issue: 7205
Pages: 766-770
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature07107
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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