title: Histone H4 lysine 16 acetylation regulates cellular lifespan.
abstract: Cells undergoing developmental processes are characterized by persistent non-genetic alterations in chromatin, termed epigenetic changes, represented by distinct patterns of DNA methylation and histone post-translational modifications. Sirtuins, a group of conserved NAD(+)-dependent deacetylases or ADP-ribosyltransferases, promote longevity in diverse organisms; however, their molecular mechanisms in ageing regulation remain poorly understood. Yeast Sir2, the first member of the family to be found, establishes and maintains chromatin silencing by removing histone H4 lysine 16 acetylation and bringing in other silencing proteins. Here we report an age-associated decrease in Sir2 protein abundance accompanied by an increase in H4 lysine 16 acetylation and loss of histones at specific subtelomeric regions in replicatively old yeast cells, which results in compromised transcriptional silencing at these loci. Antagonizing activities of Sir2 and Sas2, a histone acetyltransferase, regulate the replicative lifespan through histone H4 lysine 16 at subtelomeric regions. This pathway, distinct from existing ageing models for yeast, may represent an evolutionarily conserved function of sirtuins in regulation of replicative ageing by maintenance of intact telomeric chromatin.
authors.affiliation: Gene Expression and Regulation Program, The Wistar Institute Philadelphia, Pennsylvania 19104, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Dang
authors.forename: Kristan K
authors.initials: KK
authors.lastname: Steffen
authors.forename: Rocco
authors.initials: R
authors.lastname: Perry
authors.forename: Jean A
authors.initials: JA
authors.lastname: Dorsey
authors.forename: F Brad
authors.initials: FB
authors.lastname: Johnson
authors.forename: Ali
authors.initials: A
authors.lastname: Shilatifard
authors.forename: Matt
authors.initials: M
authors.lastname: Kaeberlein
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Berger
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism; D002455:Cell Division; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004843:Epistasis, Genetic; D015966:Gene Expression Regulation, Fungal; D020868:Gene Silencing; D051548:Histone Acetyltransferases; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000172:deficiency / Q000378:metabolism; D006657:Histones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D056565:Sirtuin 2; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D050505:Mutant Proteins; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C469266:Sas2 protein, S cerevisiae; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2; D037761:Sirtuins; D006655:Histone Deacetylases; D008239:Lysine