title: H3K36 methylation promotes longevity by enhancing transcriptional fidelity.
abstract: Epigenetic mechanisms, including histone post-translational modifications, control longevity in diverse organisms. Relatedly, loss of proper transcriptional regulation on a global scale is an emerging phenomenon of shortened life span, but the specific mechanisms linking these observations remain to be uncovered. Here, we describe a life span screen in Saccharomyces cerevisiae that is designed to identify amino acid residues of histones that regulate yeast replicative aging. Our results reveal that lack of sustained histone H3K36 methylation is commensurate with increased cryptic transcription in a subset of genes in old cells and with shorter life span. In contrast, deletion of the K36me2/3 demethylase Rph1 increases H3K36me3 within these genes, suppresses cryptic transcript initiation, and extends life span. We show that this aging phenomenon is conserved, as cryptic transcription also increases in old worms. We propose that epigenetic misregulation in aging cells leads to loss of transcriptional precision that is detrimental to life span, and, importantly, this acceleration in aging can be reversed by restoring transcriptional fidelity.
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Payel
authors.initials: P
authors.lastname: Sen
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, USA;
authors.forename: Weiwei
authors.initials: W
authors.lastname: Dang
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Greg
authors.initials: G
authors.lastname: Donahue
authors.affiliation: High-Throughput Biology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
authors.forename: Junbiao
authors.initials: J
authors.lastname: Dai
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Jean
authors.initials: J
authors.lastname: Dorsey
authors.affiliation: Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, USA;
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Cao
authors.affiliation: High-Throughput Biology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Kajia
authors.initials: K
authors.lastname: Cao
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Rocco
authors.initials: R
authors.lastname: Perry
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Jun Yeop
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington 98195, USA;
authors.forename: Brian M
authors.initials: BM
authors.lastname: Wasko
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington 98195, USA;
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Carr
authors.affiliation: The Buck Institute of Research on Aging, Novato, California 94945, USA;
authors.forename: Chong
authors.initials: C
authors.lastname: He
authors.affiliation: The Buck Institute of Research on Aging, Novato, California 94945, USA;
authors.forename: Brett
authors.initials: B
authors.lastname: Robison
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: John
authors.initials: J
authors.lastname: Wagner
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Brian D
authors.initials: BD
authors.lastname: Gregory
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington 98195, USA;
authors.forename: Matt
authors.initials: M
authors.lastname: Kaeberlein
authors.affiliation: The Buck Institute of Research on Aging, Novato, California 94945, USA;
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
authors.affiliation: High-Throughput Biology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; Institute for Systems Genetics, New York University Langone Medical Center, New York, New York 10016, USA.
authors.forename: Jef D
authors.initials: JD
authors.lastname: Boeke
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Berger
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D056466:Histone Demethylases / Q000235:genetics* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008136:Longevity / Q000235:genetics*; D008745:Methylation; D009154:Mutation; D011499:Protein Processing, Post-Translational / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics
chemical_list: D006657:Histones; C400296:RPH1 protein, S cerevisiae; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D056466:Histone Demethylases
keywords: H3K36 methylation; aging; cryptic transcription; epigenetics