title: Senescent cells harbour features of the cancer epigenome.
abstract: Altered DNA methylation and associated destabilization of genome integrity and function is a hallmark of cancer. Replicative senescence is a tumour suppressor process that imposes a limit on the proliferative potential of normal cells that all cancer cells must bypass. Here we show by whole-genome single-nucleotide bisulfite sequencing that replicative senescent human cells exhibit widespread DNA hypomethylation and focal hypermethylation. Hypomethylation occurs preferentially at gene-poor, late-replicating, lamin-associated domains and is linked to mislocalization of the maintenance DNA methyltransferase (DNMT1) in cells approaching senescence. Low-level gains of methylation are enriched in CpG islands, including at genes whose methylation and silencing is thought to promote cancer. Gains and losses of methylation in replicative senescence are thus qualitatively similar to those in cancer, and this 'reprogrammed' methylation landscape is largely retained when cells bypass senescence. Consequently, the DNA methylome of senescent cells might promote malignancy, if these cells escape the proliferative barrier.
authors.affiliation: 1] Institute of Cancer Sciences, University of Glasgow and Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK [2] [3].
authors.forename: Hazel A
authors.initials: HA
authors.lastname: Cruickshanks
authors.forename: Tony
authors.initials: T
authors.lastname: McBryan
authors.forename: David M
authors.initials: DM
authors.lastname: Nelson
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Vanderkraats
authors.forename: Parisha P
authors.initials: PP
authors.lastname: Shah
authors.forename: John
authors.initials: J
authors.lastname: van Tuyn
authors.forename: Taranjit
authors.initials: T
authors.lastname: Singh Rai
authors.forename: Claire
authors.initials: C
authors.lastname: Brock
authors.forename: Greg
authors.initials: G
authors.lastname: Donahue
authors.forename: Donncha S
authors.initials: DS
authors.lastname: Dunican
authors.forename: Mark E
authors.initials: ME
authors.lastname: Drotar
authors.forename: Richard R
authors.initials: RR
authors.lastname: Meehan
authors.forename: John R
authors.initials: JR
authors.lastname: Edwards
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Berger
authors.forename: Peter D
authors.initials: PD
authors.lastname: Adams
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics*; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015870:Gene Expression; D015894:Genome, Human; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D021381:Protein Transport
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D009419:Nerve Tissue Proteins; C105389:NEUROG1 protein, human; C000619380:DNMT1 protein, human