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

David M. Nelson, Farah Jaber-Hijazi, John J. Cole, Neil A. Robertson, Jeffrey S. Pawlikowski, Kevin T. Norris, Steven W. Criscione, Nikolay A. Pchelintsev, Desiree Piscitello, Nicholas Stong, Taranjit Singh Rai, Tony McBryan, Gabriel L. Otte, Colin Nixon, William Clark, Harold Riethman, Hong Wu, Gunnar Schotta, Benjamin A. Garcia, Nicola Neretti & 3 others Duncan M. Baird, Shelley L. Berger, Peter D. Adams

Research output: Contribution to journalArticle

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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.

LanguageEnglish
Article number158
JournalGenome Biology
Volume17
Issue number1
DOIs
Publication statusPublished - 25 Jul 2016

Fingerprint

Cell Aging
senescence
Epigenomics
epigenetics
tumor
Chromatin
chromatin
neoplasms
Neoplasms
oncogenes
cells
Oncogenes
carcinogenesis
Carcinogenesis
gene expression
Histone Code
gene
Genes
Gene Expression
cell senescence

Keywords

  • Cell senescence
  • Chromatin
  • SUV420H2/H4K20me3
  • Tumor suppression

Cite this

Nelson, David M. ; Jaber-Hijazi, Farah ; Cole, John J. ; Robertson, Neil A. ; Pawlikowski, Jeffrey S. ; Norris, Kevin T. ; Criscione, Steven W. ; Pchelintsev, Nikolay A. ; Piscitello, Desiree ; Stong, Nicholas ; Rai, Taranjit Singh ; McBryan, Tony ; Otte, Gabriel L. ; Nixon, Colin ; Clark, William ; Riethman, Harold ; Wu, Hong ; Schotta, Gunnar ; Garcia, Benjamin A. ; Neretti, Nicola ; Baird, Duncan M. ; Berger, Shelley L. ; Adams, Peter D. / 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. In: Genome Biology. 2016 ; Vol. 17, No. 1.
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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",
author = "Nelson, {David M.} and Farah Jaber-Hijazi and Cole, {John J.} and Robertson, {Neil A.} and Pawlikowski, {Jeffrey S.} and Norris, {Kevin T.} and Criscione, {Steven W.} and Pchelintsev, {Nikolay A.} and Desiree Piscitello and Nicholas Stong and Rai, {Taranjit Singh} and Tony McBryan and Otte, {Gabriel L.} and Colin Nixon and William Clark and Harold Riethman and Hong Wu and Gunnar Schotta and Garcia, {Benjamin A.} and Nicola Neretti and Baird, {Duncan M.} and Berger, {Shelley L.} and Adams, {Peter D.}",
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Nelson, DM, Jaber-Hijazi, F, Cole, JJ, Robertson, NA, Pawlikowski, JS, Norris, KT, Criscione, SW, Pchelintsev, NA, Piscitello, D, Stong, N, Rai, TS, McBryan, T, Otte, GL, Nixon, C, Clark, W, Riethman, H, Wu, H, Schotta, G, Garcia, BA, Neretti, N, Baird, DM, Berger, SL & Adams, PD 2016, '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', Genome Biology, vol. 17, no. 1, 158. https://doi.org/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. / Nelson, David M.; Jaber-Hijazi, Farah; Cole, John J.; Robertson, Neil A.; Pawlikowski, Jeffrey S.; Norris, Kevin T.; Criscione, Steven W.; Pchelintsev, Nikolay A.; Piscitello, Desiree; Stong, Nicholas; Rai, Taranjit Singh; McBryan, Tony; Otte, Gabriel L.; Nixon, Colin; Clark, William; Riethman, Harold; Wu, Hong; Schotta, Gunnar; Garcia, Benjamin A.; Neretti, Nicola; Baird, Duncan M.; Berger, Shelley L.; Adams, Peter D.

In: Genome Biology, Vol. 17, No. 1, 158, 25.07.2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Nelson, David M.

AU - Jaber-Hijazi, Farah

AU - Cole, John J.

AU - Robertson, Neil A.

AU - Pawlikowski, Jeffrey S.

AU - Norris, Kevin T.

AU - Criscione, Steven W.

AU - Pchelintsev, Nikolay A.

AU - Piscitello, Desiree

AU - Stong, Nicholas

AU - Rai, Taranjit Singh

AU - McBryan, Tony

AU - Otte, Gabriel L.

AU - Nixon, Colin

AU - Clark, William

AU - Riethman, Harold

AU - Wu, Hong

AU - Schotta, Gunnar

AU - Garcia, Benjamin A.

AU - Neretti, Nicola

AU - Baird, Duncan M.

AU - Berger, Shelley L.

AU - Adams, Peter D.

PY - 2016/7/25

Y1 - 2016/7/25

N2 - 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.

AB - 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.

KW - Cell senescence

KW - Chromatin

KW - SUV420H2/H4K20me3

KW - Tumor suppression

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