title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK.|Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Nelson
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK.|Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK.
authors.forename: Farah
authors.initials: F
authors.lastname: Jaber-Hijazi
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK.|Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK.
authors.forename: John J
authors.initials: JJ
authors.lastname: Cole
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK.|Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Robertson
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK.|Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Pawlikowski
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Norris
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, 02903, USA.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Criscione
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK.|Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK.
authors.forename: Nikolay A
authors.initials: NA
authors.lastname: Pchelintsev
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK.|Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK.
authors.forename: Desiree
authors.initials: D
authors.lastname: Piscitello
authors.affiliation: The Wistar Institute, Philadelphia, PA, 19104, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stong
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK.|Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK.|Institute of Biomedical and Environmental Health Research, University of the West of Scotland, Paisley, PA1 2BE, UK.
authors.forename: Taranjit Singh
authors.initials: TS
authors.lastname: Rai
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK.|Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK.
authors.forename: Tony
authors.initials: T
authors.lastname: McBryan
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Gabriel L
authors.initials: GL
authors.lastname: Otte
authors.affiliation: Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Nixon
authors.affiliation: Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK.
authors.forename: William
authors.initials: W
authors.lastname: Clark
authors.affiliation: The Wistar Institute, Philadelphia, PA, 19104, USA.
authors.forename: Harold
authors.initials: H
authors.lastname: Riethman
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Ludwig Maximilians University and Munich Center for Integrated Protein Science (CiPSM), Biomedical Center, Planegg-Martinsried, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Schotta
authors.affiliation: Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Garcia
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, 02903, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Neretti
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK.
authors.forename: Duncan M
authors.initials: DM
authors.lastname: Baird
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Berger
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK. p.adams@beatson.gla.ac.uk.|Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK. p.adams@beatson.gla.ac.uk.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Adams
mesh_terms: D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D002843:Chromatin / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006570:Heterochromatin / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006657:Histones / Q000235:genetics; D006801:Humans; D009506:Nevus / Q000378:metabolism / Q000473:pathology
chemical_list: D002843:Chromatin; D006570:Heterochromatin; D006657:Histones; D011495:Histone-Lysine N-Methyltransferase
keywords: Cell senescence; Chromatin; SUV420H2/H4K20me3; Tumor suppression