Abstract

Altered DNA methylation and associated destabilization of genome integrity and function is a hallmark of cancer. Replicative senescence is a tumour suppressor process that imposes a limit on the proliferative potential of normal cells that all cancer cells must bypass. Here we show by whole-genome single-nucleotide bisulfite sequencing that replicative senescent human cells exhibit widespread DNA hypomethylation and focal hypermethylation. Hypomethylation occurs preferentially at gene-poor, late-replicating, lamin-associated domains and is linked to mislocalization of the maintenance DNA methyltransferase (DNMT1) in cells approaching senescence. Low-level gains of methylation are enriched in CpG islands, including at genes whose methylation and silencing is thought to promote cancer. Gains and losses of methylation in replicative senescence are thus qualitatively similar to those in cancer, and this ‘reprogrammed’ methylation landscape is largely retained when cells bypass senescence. Consequently, the DNA methylome of senescent cells might promote malignancy, if these cells escape the proliferative barrier.

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Acknowledgements

Thanks to S. Pepper in the CRUK microarray facility and to S. Hansen for assistance with DNA replication timing data. Thanks to Beijing Genome Institute for bisulfite sequencing. Work in the laboratory of P.D.A. was funded by NIA Program Project P01 AG031862 and CRUK Program A10250. S.L.B.’s laboratory was funded by NIA Program Project P01 AG031862. R.R.M.’s laboratory was funded by the MRC and the BBSRC. P.D.A. thanks P. Cairns for critical formative discussions.

Author information

Author notes

    • Hazel A. Cruickshanks
    •  & Taranjit Singh Rai

    Present addresses: MRC Human Genetics Unit at the Institute of Genetics and Molecular Medicine at the University of Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK; (H.A.C.); Institute of Biomedical and Environmental Health Research, University of the West of Scotland, Paisley, PA1 2BE, UK (T.S.R.)

    • Hazel A. Cruickshanks
    •  & Tony McBryan

    These authors contributed equally to this work

Affiliations

  1. Institute of Cancer Sciences, University of Glasgow and Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK

    • Hazel A. Cruickshanks
    • , Tony McBryan
    • , David M. Nelson
    • , John van Tuyn
    • , Taranjit Singh Rai
    • , Claire Brock
    • , Mark E. Drotar
    •  & Peter D. Adams
  2. Center for Pharmacogenomics, Washington University School of Medicine, St Louis, Missouri 63110, USA

    • Nathan D. VanderKraats
    •  & John R. Edwards
  3. Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Parisha P. Shah
    • , Greg Donahue
    •  & Shelley L. Berger
  4. MRC Human Genetics Unit at the Institute of Genetics and Molecular Medicine at the University of Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK

    • Donncha S. Dunican
    •  & Richard R. Meehan

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Contributions

H.A.C. carried out the bulk of the experiments. D.M.N., P.P.S., J.v.T., T.S.R., C.B., M.E.D. and D.S.D. carried out further experiments. T.M. carried out the bulk of the data analysis. N.D.V. and G.D. carried out further data analyses. H.A.C. and T.M. provided substantial and critical intellectual input. R.R.M., J.R.E. and S.L.B. provided further intellectual input. P.D.A., H.A.C. and T.M. conceived the project and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Peter D. Adams.

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https://doi.org/10.1038/ncb2879

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