Senescent cells harbour features of the cancer epigenome

Hazel A. Cruickshanks, Tony McBryan, David M. Nelson, Nathan D. Vanderkraats, Parisha P. Shah, John van Tuyn, Taranjit Singh Rai, Claire Brock, Greg Donahue, Donncha S. Dunican, Mark E. Drotar, Richard R. Meehan, John R. Edwards, Shelley L. Berger, Peter D. Adams

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1495-1506
Number of pages12
JournalNature Cell Biology
Volume15
DOIs
Publication statusPublished - 24 Nov 2013
Externally publishedYes

Fingerprint

Cell Aging
Methylation
Neoplasms
DNA
Genome
Lamins
CpG Islands
Methyltransferases
DNA Methylation
Genes
Nucleotides
Maintenance

Keywords

  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Aging
  • Cell Cycle Proteins
  • Cell Line
  • CpG Islands
  • DNA (Cytosine-5-)-Methyltransferase
  • DNA Methylation
  • Epigenesis, Genetic
  • Gene Expression
  • Genome, Human
  • Humans
  • Neoplasms
  • Nerve Tissue Proteins
  • Promoter Regions, Genetic
  • Protein Transport

Cite this

Cruickshanks, H. A., McBryan, T., Nelson, D. M., Vanderkraats, N. D., Shah, P. P., van Tuyn, J., ... Adams, P. D. (2013). Senescent cells harbour features of the cancer epigenome. Nature Cell Biology, 15, 1495-1506. https://doi.org/10.1038/ncb2879
Cruickshanks, Hazel A. ; McBryan, Tony ; Nelson, David M. ; Vanderkraats, Nathan D. ; Shah, Parisha P. ; van Tuyn, John ; Singh Rai, Taranjit ; Brock, Claire ; Donahue, Greg ; Dunican, Donncha S. ; Drotar, Mark E. ; Meehan, Richard R. ; Edwards, John R. ; Berger, Shelley L. ; Adams, Peter D. / Senescent cells harbour features of the cancer epigenome. In: Nature Cell Biology. 2013 ; Vol. 15. pp. 1495-1506.
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Cruickshanks, HA, McBryan, T, Nelson, DM, Vanderkraats, ND, Shah, PP, van Tuyn, J, Singh Rai, T, Brock, C, Donahue, G, Dunican, DS, Drotar, ME, Meehan, RR, Edwards, JR, Berger, SL & Adams, PD 2013, 'Senescent cells harbour features of the cancer epigenome', Nature Cell Biology, vol. 15, pp. 1495-1506. https://doi.org/10.1038/ncb2879

Senescent cells harbour features of the cancer epigenome. / Cruickshanks, Hazel A.; McBryan, Tony; Nelson, David M.; Vanderkraats, Nathan D.; Shah, Parisha P.; van Tuyn, John; Singh Rai, Taranjit; Brock, Claire; Donahue, Greg; Dunican, Donncha S.; Drotar, Mark E.; Meehan, Richard R.; Edwards, John R.; Berger, Shelley L.; Adams, Peter D.

In: Nature Cell Biology, Vol. 15, 24.11.2013, p. 1495-1506.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Senescent cells harbour features of the cancer epigenome

AU - Cruickshanks, Hazel A.

AU - McBryan, Tony

AU - Nelson, David M.

AU - Vanderkraats, Nathan D.

AU - Shah, Parisha P.

AU - van Tuyn, John

AU - Singh Rai, Taranjit

AU - Brock, Claire

AU - Donahue, Greg

AU - Dunican, Donncha S.

AU - Drotar, Mark E.

AU - Meehan, Richard R.

AU - Edwards, John R.

AU - Berger, Shelley L.

AU - Adams, Peter D.

PY - 2013/11/24

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AB - 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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KW - Cell Line

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KW - DNA (Cytosine-5-)-Methyltransferase

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KW - Epigenesis, Genetic

KW - Gene Expression

KW - Genome, Human

KW - Humans

KW - Neoplasms

KW - Nerve Tissue Proteins

KW - Promoter Regions, Genetic

KW - Protein Transport

U2 - 10.1038/ncb2879

DO - 10.1038/ncb2879

M3 - Article

VL - 15

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EP - 1506

JO - Nature Cell Biology

JF - Nature Cell Biology

SN - 1465-7392

ER -

Cruickshanks HA, McBryan T, Nelson DM, Vanderkraats ND, Shah PP, van Tuyn J et al. Senescent cells harbour features of the cancer epigenome. Nature Cell Biology. 2013 Nov 24;15:1495-1506. https://doi.org/10.1038/ncb2879