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,Peter D Adams,Nikolay A Pchelintsev,Colin Nixon,Steven W Criscione,Harold Riethman,Shelley L Berger,Nicholas Stong,Nicola Neretti,Benjamin A Garcia,Farah Jaber-Hijazi,William Clark,Jeffrey S Pawlikowski,Tony Mcbryan,Gunnar Schotta,John Cole ,Taranjit Singh ,D Piscitello ,Gabriel Otte ,Neil Robertson ,Hong Gyun Wu ,Kevin Norris ,Duncan Martin Baird

doi:10.1186/s13059-016-1017-x

Abstract

BackgroundHistone 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.ResultsUsing 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1017-x) contains supplementary material, which is available to authorized users.

Highlights

Histone modification H4K20me3 and its methyltransferase SUV420H2 have been implicated in suppression of tumorigenesis
We propose that elevated H4K20me3 in senescent cells contributes, at least in part, to stabilization of the senescent epigenome and genome, thereby stabilizing the senescent phenotype and, long-term senescence-mediated tumor suppression
Senescent cells accumulate elevated levels of H4K20me3 In order to investigate the potential contribution of H4K20me3 to the senescence program, we first set out to better characterize the regulation and distribution of the mark in senescent cells in vitro

Summary

Introduction

Histone modification H4K20me and its methyltransferase SUV420H2 have been implicated in suppression of tumorigenesis. The underlying mechanism is unclear, H4K20me abundance increases during cellular senescence, a stable proliferation arrest and tumor suppressor process, triggered by diverse molecular cues, including activated oncogenes. Cellular senescence is a stable proliferation arrest associated with an altered pro-inflammatory secretory pathway and an important tumor suppressor mechanism [1, 2]. Chromatin changes in senescent cells are perhaps best illustrated by senescence-associated heterochromatin foci (SAHF) [15]. These punctate heterochromatic foci have been proposed to promote silencing of proliferation-promoting genes and/or dampen the DNA damage response in senescent cells to maintain cell viability [15, 25]. SAHF exhibit a layered structure comprised of an H3K9me3-rich core of DNA that ordinarily replicates late in S phase in proliferating cells surrounded by an outer H3K27me3rich domain [18]

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