Senescent cells harbour features of the cancer epigenome
Open accessAbstract
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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The DNA methylation profile of senescence somewhat resembles cancer- and aging-associated methylome patterns.
“Interestingly, this DNA methylation profile somewhat resembles the cancer- and aging-associated methylome patterns (Cruickshanks et al., 2013; Xie et al., 2018).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Cruickshanks et al., 2013
The Results section, “Methylation changes in senescence resemble those in cancer” (page unavailable), reports a partial but highly significant overlap between methylation changes in senescent cells and cancer cells. The paper also notes earlier findings of declining overall methylation in cultured primary human cells, but our copy does not establish a broader resemblance to aging-associated methylome patterns. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDecompacted hSATII loci are a characteristic feature of senescent fibroblasts.
“These findings suggest that decompacted hSATII loci are a characteristic feature of senescent fibroblasts, consistent with previous reports on satellite distension during senescence (23–25).”
From Chromatin conformational changes at human satellite II contribute to the senescence phenotype in the tumor microenvironment (2023) · cites this paper as [25]
During replicative senescence, late-replicating gene-poor regions show widespread DNA hypomethylation, while tumour suppressor genes show focal hypermethylation.
“During replicative senescence, late-replicating, gene-poor regions display widespread DNA hypomethylation, whereas focal hypermethylation is seen at tumour suppressor genes”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [64]
Senescence-associated distension of satellites corresponds to de-compaction of (peri-)centric constitutive heterochromatin.
“Another chromatin feature, termed senescence-associated distension of satellites (SADSs), corresponds to de-compaction of (peri-)centric constitutive heterochromatin (Cruickshanks et al., 2013; De Cecco et al., 2013; Swanson et al., 2013).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Cruickshanks et al., 2013
Cellular senescence entails focal increases in DNA methylation at certain CpG islands.
“In addition to the global loss of DNA methylation, cellular senescence entails focal increases in DNA methylation at certain CpG islands (Cruickshanks et al., 2013).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Cruickshanks et al., 2013
DNA methylation changes are early events in senescence, whereas retrotransposon activation occurs only much later.
“However, DNA methylation changes are early events in senescence73, whereas retrotransposon activation occurs only much later33.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [73]
hSATII transcription is elevated in senescent and tumor cells.
“hSATII transcription is elevated in senescent (11, 23, 25, 26) and tumor cells (27–32)”
From Chromatin conformational changes at human satellite II contribute to the senescence phenotype in the tumor microenvironment (2023) · cites this paper as [25]
In near-senescent cells, DNMT1 cannot localize to hSATII loci, which might result in overt hypomethylation.
“Cruickshanks et al. suggested that in near-senescent cells, DNA methyltransferase 1 (DNMT1) cannot localize to the hSATII loci. This might result in overt hypomethylation (25)”
From Chromatin conformational changes at human satellite II contribute to the senescence phenotype in the tumor microenvironment (2023) · cites this paper as [25]
Alterations in DNA methylation are observed during replicative senescence, whereas cells undergoing oncogene induced senescence do not show such alterations in DNA methylation.
“Alterations in DNA methylation are observed during replicative senescence whereas cells undergoing oncogene induced senescence do not show any such alterations in DNA methylation (Cruickshanks et al., 2013; Cheng et al., 2017; Xie et al., 2018).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Cruickshanks et al., 2013
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- Authors
- Cruickshanks, H. A., McBryan, T., Nelson, D. M., VanderKraats, N. D., Shah, P. P., van Tuyn, J., Singh Rai, T., Brock, C., Donahue, G., Dunican, D. S., Drotar, M. E., Meehan, R. R., Edwards, J. R., Berger, S. L., & Adams, P. D.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- Washington University in St. Louis (US)
- University of Pennsylvania (US)
- Institute of Genetics and Cancer (GB)
- Corresponding author
- Adams, Peter D.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2013-11-24
- Volume
- 15
- Issue
- 12
- Pages
- 1495-1506
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4106249
- OpenAlex
- W2085683078
- Cited by
- 358
- References
- 71
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 32 · 2023: 32 · 2022: 29 · 2021: 37 · 2020: 37 · 2019: 26 · 2018: 29 · 2017: 24 · 2016: 25 · 2015: 27 · 2014: 19 · 2013: 2
- FWCI
- 10.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council (BB/J021032/1)
- National Institute on Aging (P01AG031862)
- U.S. National Library of Medicine (R21LM011199)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- replicative senescence, DNA methylation, DNA hypomethylation, DNA hypermethylation, cancer epigenome, lamin-associated domains, CpG islands, senescence escape, p53 inactivation, pRb inactivation, tumour suppressor, methylome
- MeSH terms
- DNA (Cytosine-5-)-Methyltransferase 1, Cell Line, DNA (Cytosine-5-)-Methyltransferases, Humans, Neoplasms, Nerve Tissue Proteins, Promoter Regions, Genetic, Gene Expression, Genome, Human, Cellular Senescence, Cell Cycle Proteins, CpG Islands, DNA Methylation, Protein Transport, Epigenesis, Genetic, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors
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