title: Implications of time-series gene expression profiles of replicative senescence.
abstract: Although senescence has long been implicated in aging-associated pathologies, it is not clearly understood how senescent cells are linked to these diseases. To address this knowledge gap, we profiled cellular senescence phenotypes and mRNA expression patterns during replicative senescence in human diploid fibroblasts. We identified a sequential order of gain-of-senescence phenotypes: low levels of reactive oxygen species, cell mass/size increases with delayed cell growth, high levels of reactive oxygen species with increases in senescence-associated β-galactosidase activity (SA-β-gal), and high levels of SA-β-gal activity. Gene expression profiling revealed four distinct modules in which genes were prominently expressed at certain stages of senescence, allowing us to divide the process into four stages: early, middle, advanced, and very advanced. Interestingly, the gene expression modules governing each stage supported the development of the associated senescence phenotypes. Senescence-associated secretory phenotype-related genes also displayed a stage-specific expression pattern with three unique features during senescence: differential expression of interleukin isoforms, differential expression of interleukins and their receptors, and differential expression of matrix metalloproteinases and their inhibitory proteins. We validated these phenomena at the protein level using human diploid fibroblasts and aging Sprague-Dawley rat skin tissues. Finally, disease-association analysis of the modular genes also revealed stage-specific patterns. Taken together, our results reflect a detailed process of cellular senescence and provide diverse genome-wide information of cellular backgrounds for senescence.
authors.affiliation: Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, 443-721, Korea.
authors.forename: You-Mie
authors.initials: YM
authors.lastname: Kim
authors.forename: Hae-Ok
authors.initials: HO
authors.lastname: Byun
authors.forename: Byul A
authors.initials: BA
authors.lastname: Jee
authors.forename: Hyunwoo
authors.initials: H
authors.lastname: Cho
authors.forename: Yong-Hak
authors.initials: YH
authors.lastname: Seo
authors.forename: You-Sun
authors.initials: YS
authors.lastname: Kim
authors.forename: Min Hi
authors.initials: MH
authors.lastname: Park
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Chung
authors.forename: Hyun Goo
authors.initials: HG
authors.lastname: Woo
authors.forename: Gyesoon
authors.initials: G
authors.lastname: Yoon
mesh_terms: D000818:Animals; D002453:Cell Cycle; D016923:Cell Death; D048429:Cell Size; D016922:Cellular Senescence; D004171:Diploidy; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D059467:Transcriptome; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D007378:Interleukins; D017382:Reactive Oxygen Species; D001616:beta-Galactosidase; D053508:Matrix Metalloproteinase 12
keywords: gene expression; human diploid fibroblasts; replicative senescence; senescence-associated secretory phenotype