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Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements
Open accessAbstract
Summary: Replicative cellular senescence is an important tumor suppression mechanism and also contributes to aging. Progression of both cancer and aging include significant epigenetic components, but the chromatin changes that take place during cellular senescence are not known. We used formaldehyde assisted isolation of regulatory elements ( FAIRE ) to map genome‐wide chromatin conformations. In contrast to growing cells, whose genomes are rich with features of both open and closed chromatin, FAIRE profiles of senescent cells are significantly smoothened. This is due to FAIRE signal loss in promoters and enhancers of active genes, and FAIRE signal gain in heterochromatic gene‐poor regions. Chromatin of major retrotransposon classes, Alu, SVA and L1, becomes relatively more open in senescent cells, affecting most strongly the evolutionarily recent elements, and leads to an increase in their transcription and ultimately transposition. Constitutive heterochromatin in centromeric and peri‐centromeric regions also becomes relatively more open, and the transcription of satellite sequences increases. The peripheral heterochromatic compartment ( PHC ) becomes less prominent, and centromere structure becomes notably enlarged. These epigenetic changes progress slowly after the onset of senescence, with some, such as mobilization of retrotransposable elements becoming prominent only at late times. Many of these changes have also been noted in cancer cells.
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“oncogene-induced senescent cells and late replicatively senescent fibroblasts exhibit a marked increase in chromatin accessibility at the nucleosomal level, with most of the open chromatin regions mapping to regulatory elements and repeats66,67”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [67]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Senescent cells also exhibit a global increase in chromatin accessibility, but the genome-wide profile varies depending on the stimulus (De Cecco et al., 2013).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as De Cecco et al., 2013
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The normally repressed LINE-1 (L1) retrotransposons are activated, stimulating the cGAS-STING pathway that elicits a type 1 interferon response (see Secretion) (De Cecco et al., 2013).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as De Cecco et al., 2013
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Retrotransposons become reactivated in cell senescence and with age in both mammals and Drosophila58, 60, 66, 68.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [66]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The ability of STORM to provide a detailed rendering of the structure of chromatin fibers37 makes it ideal to investigate changes in heterochromatin distribution within senescent nuclei, such as the loss of lamin-associated domains38, which has been primarily investigated via electron microscopy techniques39.”
From Spatial mapping of cellular senescence: emerging challenges and opportunities (2023) · cites this paper as [39]
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“A conserved feature of aging is the progressive increase in retrotransposon transcript levels, particularly the ERV class of LTR retrotransposons”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as De Cecco et al. 2013
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“this study builds on the mounting body of evidence which suggests that L1s become more transcriptionally active during aging and senescence10,49”
From SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age (2014) · cites this paper as [10]
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“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 [23]
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“Chromatin loosening at genomic repeats results in increased expression levels of transposable elements, which are normally epigenetically silenced and dormant in unstressed cells67”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [67]
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“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 De Cecco et al., 2013
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“Increased chromatin accessibility of the pericentromeric hSATII loci in senescent fibroblasts as determined by formaldehyde-assisted isolation of regulatory element sequencing (23) and assay for transposase-accessible chromatin with sequencing (ATAC-seq) validated this distention (11, 21).”
From Chromatin conformational changes at human satellite II contribute to the senescence phenotype in the tumor microenvironment (2023) · cites this paper as [23]
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“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 [23]
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“Although the hSATII DNA is generally silenced by heterochromatinization, it adopts a dramatically open conformation in senescent human diploid fibroblasts as determined by DNA-fluorescence in situ hybridization (DNA-FISH) (23).”
From Chromatin conformational changes at human satellite II contribute to the senescence phenotype in the tumor microenvironment (2023) · cites this paper as [23]
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“The decondensation of these heterochromatic regions is associated with expression of transposable elements (such as LINE1 elements) and their transposition, particularly at later time points after the induction of senescence.”
From Cellular senescence and its effector programs (2014) · cites this paper as De Cecco et al. 2013
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“On the other hand, chromatin of repetitive sequences, including major classes of retrotransposon as well as pericentromeric regions, which are highly condensed in normal cells, tend to become open in senescent cells.”
From Cellular senescence and its effector programs (2014) · cites this paper as De Cecco et al. 2013
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“They showed, in replicative senescent HDFs, an overall condensation of chromatin in euchromatic regions, with the exception of some specific genes.”
From Cellular senescence and its effector programs (2014) · cites this paper as De Cecco et al. 2013
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“evidence has begun to accumulate indicating that the mechanisms which silence retrotransposons in somatic cells are not completely efficient9 and may deteriorate with age10,11.”
From SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age (2014) · cites this paper as [10]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Primer sequences were analyzed using the UCSC genome browser in silico PCR tool (genome.ucsc.edu/cgi-bin/hgPcr) to determine the number of genomic elements that contribute to the amplification products (De Cecco et al., 2013).”
From Loss of epigenetic information as a cause of mammalian aging (2023) · cites this paper as De Cecco et al., 2013
Experimental — accuracy not yet measuredIn the citing paper
“Transposons (“jumping genes”) can be produced within senescent cells that re-insert into senescent cell DNA, contributing to the senescent cell phenotype and exacerbating their SASP [24, 25].”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [24]
In the citing paper
“the chromatin at transposable elements (Alu, L1, and SVA) becomes more open (De Cecco et al., 2013).”
From The Aging Epigenome (2016) · cites this paper as De Cecco et al., 2013
In the citing paper
“the expression of these repetitive DNA elements also increases in senescent cells (De Cecco et al., 2013).”
From The Aging Epigenome (2016) · cites this paper as De Cecco et al., 2013
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Citations
Cites
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“Subsequently it has emerged as a potent tumor suppression mechanism, and recent evidence points to important connections with aging (Collado et al., 2007; Baker et al., 2011).”
BackgroundMapping and analysis of chromatin state dynamics in nine human cell types
Ernst, J., Kheradpour, P., Mikkelsen, T. S., Shoresh, N., Ward, L. D., Epstein, C. B., Zhang, X., Wang, L., Issner, R., Coyne, M., et al. (2011) · Nature · doi:10.1038/nature09906 · Cited by 2,898
Histone modifications at human enhancers reflect global cell-type-specific gene expression
Heintzman, N. D., Hon, G. C., Hawkins, R. D., Kheradpour, P., Stark, A., Harp, L. F., Ye, Z., Lee, L. K., Stuart, R. K., Ching, C. W., et al. (2009) · Nature · doi:10.1038/nature07829 · Cited by 2,533
Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence
Narita, M., Nuñez, S., Heard, E., Narita, M., Lin, A. W., Hearn, S. A., Spector, D. L., Hannon, G. J., & Lowe, S. W. (2003) · Cell · doi:10.1016/s0092-8674(03)00401-x · Cited by 2,278 · cited 1×
“Formation of a distinctive type of heterochromatin known as senescence-associated heterochromatin foci (SAHF) is an important component of cellular senescence (Narita et al., 2003; Zhang et al., 2005).”
BackgroundFour faces of cellular senescence
Rodier, F., & Campisi, J. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201009094 · Cited by 2,070 · cited 1×
“Many forms of oncogene-induced senescence have also been associated with the induction of the DNA damage response (Rodier & Campisi, 2011).”
BackgroundRegulation of Heterochromatic Silencing and Histone H3 Lysine-9 Methylation by RNAi
Volpe, T. A., Kidner, C. A., Hall, I. M., Teng, G., Grewal, S. I. S., & Martienssen, R. A. (2002) · Science · doi:10.1126/science.1074973 · Cited by 2,055
Applied Smoothing Techniques for Data Analysis
BOWMAN, A. W., & Azzalini, A. (1997) · doi:10.1093/oso/9780198523963.001.0001 · Cited by 1,820
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Cellular Senescence: Defining a Path Forward
Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., Campisi, J., Collado, M., Evangelou, K., Ferbeyre, G., et al. (2019) · Cell · doi:10.1016/j.cell.2019.10.005 · Cited by 3,225
Self-citationThe role of senescent cells in ageing
van Deursen, J. M. (2014) · Nature · doi:10.1038/nature13193 · Cited by 2,623
Cellular senescence in ageing: from mechanisms to therapeutic opportunities
Di Micco, R., Krizhanovsky, V., Baker, D., & d’Adda di Fagagna, F. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00314-w · Cited by 2,277
Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Kumari, R., & Jat, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645593 · Cited by 1,622
Ten things you should know about transposable elements
Bourque, G., Burns, K. H., Gehring, M., Gorbunova, V., Seluanov, A., Hammell, M., Imbeault, M., Izsvák, Z., Levin, H. L., Macfarlan, T. S., et al. (2018) · Genome Biology · doi:10.1186/s13059-018-1577-z · Cited by 1,430
Metadata
- Authors
- De Cecco, M., Criscione, S. W., Peckham, E. J., Hillenmeyer, S., Hamm, E. A., Manivannan, J., Peterson, A. L., Kreiling, J. A., Neretti, N., & Sedivy, J. M.
- Affiliations
- Department of Molecular Biology, Cell Biology and Biochemistry, Center for Genomics and Proteomics Brown University Providence 02912 RI USA
- Brown University (US)
- Corresponding author
- Neretti, Nicola
- Sedivy, John M.
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2013-01-30
- Volume
- 12
- Issue
- 2
- Pages
- 247-256
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC3618682
- OpenAlex
- W2065557328
- Cited by
- 459
- References
- 51
- Citations by year
- 2026: 21 · 2025: 41 · 2024: 51 · 2023: 34 · 2022: 38 · 2021: 42 · 2020: 43 · 2019: 33 · 2018: 34 · 2017: 30 · 2016: 29 · 2015: 25 · 2014: 24 · 2013: 12
- FWCI
- 20.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (K25AG028753, R37AG016694, K01AG039410)
- National Institute of General Medical Sciences (P30GM103410, P30 GM0103410, T32GM007601)
- National Center for Research Resources (P20RR015578)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- epigenetic modifications, chromatin conformation, FAIRE, transposable elements, Alu elements, SVA elements, heterochromatin, centromere, satellite DNA, gene silencing, tumor suppression, aging
- MeSH terms
- Cells, Cultured, Centromere, DNA Transposable Elements, Fibroblasts, Formaldehyde, Heterochromatin, Humans, Transcription, Genetic, Gene Expression, Genome, Human, Cellular Senescence, Oligonucleotide Array Sequence Analysis, Gene Silencing, Euchromatin, Epigenesis, Genetic, Regulatory Elements, Transcriptional
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