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Genome Biol. 2016 Jul 25;17(1):158. doi: 10.1186/s13059-016-1017-x.

Mapping H4K20me3 onto the chromatin landscape of senescent cells indicates a function in control of cell senescence and tumor suppression through preservation of genetic and epigenetic stability.

Author information

1
Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK.
2
Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK.
3
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK.
4
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, 02903, USA.
5
The Wistar Institute, Philadelphia, PA, 19104, USA.
6
Institute of Biomedical and Environmental Health Research, University of the West of Scotland, Paisley, PA1 2BE, UK.
7
Epigenetics Program, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
8
Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
9
Ludwig Maximilians University and Munich Center for Integrated Protein Science (CiPSM), Biomedical Center, Planegg-Martinsried, Germany.
10
Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
11
Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK. p.adams@beatson.gla.ac.uk.
12
Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK. p.adams@beatson.gla.ac.uk.

Abstract

BACKGROUND:

Histone modification H4K20me3 and its methyltransferase SUV420H2 have been implicated in suppression of tumorigenesis. The underlying mechanism is unclear, although H4K20me3 abundance increases during cellular senescence, a stable proliferation arrest and tumor suppressor process, triggered by diverse molecular cues, including activated oncogenes. Here, we investigate the function of H4K20me3 in senescence and tumor suppression.

RESULTS:

Using immunofluorescence and ChIP-seq we determine the distribution of H4K20me3 in proliferating and senescent human cells. Altered H4K20me3 in senescence is coupled to H4K16ac and DNA methylation changes in senescence. In senescent cells, H4K20me3 is especially enriched at DNA sequences contained within specialized domains of senescence-associated heterochromatin foci (SAHF), as well as specific families of non-genic and genic repeats. Altered H4K20me3 does not correlate strongly with changes in gene expression between proliferating and senescent cells; however, in senescent cells, but not proliferating cells, H4K20me3 enrichment at gene bodies correlates inversely with gene expression, reflecting de novo accumulation of H4K20me3 at repressed genes in senescent cells, including at genes also repressed in proliferating cells. Although elevated SUV420H2 upregulates H4K20me3, this does not accelerate senescence of primary human cells. However, elevated SUV420H2/H4K20me3 reinforces oncogene-induced senescence-associated proliferation arrest and slows tumorigenesis in vivo.

CONCLUSIONS:

These results corroborate a role for chromatin in underpinning the senescence phenotype but do not support a major role for H4K20me3 in initiation of senescence. Rather, we speculate that H4K20me3 plays a role in heterochromatinization and stabilization of the epigenome and genome of pre-malignant, oncogene-expressing senescent cells, thereby suppressing epigenetic and genetic instability and contributing to long-term senescence-mediated tumor suppression.

KEYWORDS:

Cell senescence; Chromatin; SUV420H2/H4K20me3; Tumor suppression

PMID:
27457071
PMCID:
PMC4960804
DOI:
10.1186/s13059-016-1017-x
[Indexed for MEDLINE]
Free PMC Article

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