Genome-scale DNA methylation maps of pluripotent and differentiated cells (original) (raw)

• Letter
• Published: 06 July 2008
• Tarjei S. Mikkelsen2,4 na1,
• Hongcang Gu2,
• Marius Wernig1,
• Jacob Hanna1,
• Andrey Sivachenko2,
• Xiaolan Zhang2,
• Bradley E. Bernstein2,5,6,
• Chad Nusbaum2,
• David B. Jaffe2,
• Andreas Gnirke2,
• Rudolf Jaenisch1,7 &
• …
• Eric S. Lander1,2,7,8

Nature volume 454, pages 766–770 (2008)Cite this article

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Abstract

DNA methylation is essential for normal development1,2,3 and has been implicated in many pathologies including cancer4,5. 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 sequencing6 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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Primary accessions

Gene Expression Omnibus

Data deposits

All primary sequencing data have been submitted to the NCBI GEO repository under accession numbers GSE11034 (RRBS), GSE11172 (ChIP-Seq) and GSE11483 (gene expression microarrays).

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Acknowledgements

We thank the staff of the Broad Institute Genome Sequencing Platform for assistance with data generation and B. Ramsahoye for the nearest neighbour analysis. This research was supported by funds from the National Human Genome Research Institute, the National Cancer Institute, and the Broad Institute of MIT and Harvard.

Author information

Author notes

1. Alexander Meissner and Tarjei S. Mikkelsen: These authors contributed equally to this work.

Authors and Affiliations

1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA ,
   Alexander Meissner, Marius Wernig, Jacob Hanna, Rudolf Jaenisch & Eric S. Lander
2. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA ,
   Alexander Meissner, Tarjei S. Mikkelsen, Hongcang Gu, Andrey Sivachenko, Xiaolan Zhang, Bradley E. Bernstein, Chad Nusbaum, David B. Jaffe, Andreas Gnirke & Eric S. Lander
3. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA,
   Alexander Meissner
4. Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,
   Tarjei S. Mikkelsen
5. Molecular Pathology Unit and Center for Cancer Research, MGH, Charlestown, Massachusetts 02129, USA ,
   Bradley E. Bernstein
6. Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA,
   Bradley E. Bernstein
7. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,
   Rudolf Jaenisch & Eric S. Lander
8. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02114, USA,
   Eric S. Lander

Authors

1. Alexander Meissner
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2. Tarjei S. Mikkelsen
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3. Hongcang Gu
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4. Marius Wernig
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5. Jacob Hanna
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6. Andrey Sivachenko
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7. Xiaolan Zhang
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8. Bradley E. Bernstein
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9. Chad Nusbaum
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10. David B. Jaffe
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11. Andreas Gnirke
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12. Rudolf Jaenisch
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13. Eric S. Lander
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Corresponding authors

Correspondence toRudolf Jaenisch or Eric S. Lander.

Supplementary information

Supplementary Information 1

This file contains Supplementary Tables S1-S7 and Supplementary Figures S1-S9 with Legends. (PDF 11442 kb)

Supplementary Information 2

The file contains Supplementary Data S1. DNA and histone methylation states, and associated expression levels, for all analyzed high-CpG density promoters. (XLS 5606 kb)

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Meissner, A., Mikkelsen, T., Gu, H. et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells.Nature 454, 766–770 (2008). https://doi.org/10.1038/nature07107

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• Received: 24 March 2008
• Accepted: 21 May 2008
• Published: 06 July 2008
• Issue Date: 07 August 2008
• DOI: https://doi.org/10.1038/nature07107

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Editorial Summary

DNA methylation mapped

DNA methylation, an important mechanism of epigenetic modification that produces different patterns of gene expression from a single DNA sequence, is vital to normal development and its malfunction can cause cancer and other abnormalities. A map of DNA methylation in embryonic stem cells, and in various cell types derived from them, has now been produced at nucleotide resolution using high-throughput bisulphite sequencing combined with single molecule-based sequencing. The map reveals specific sites in the genome where methylation changes as cells develop, for instance when embryonic stem cells mature into nerve cells. More generally, the methodology will be of value for the epigenetic profiling of cell populations relevant to developmental biology, cancer and regenerative medicine.

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