title: Epigenetic regulation of tissue factor inducibility in endothelial cell senescence.
abstract: Cellular senescence, a programmed state induced by multiple deleterious triggers, is characterised by permanent cell-cycle exit and altered gene expression and cell morphology. In humans it is considered a tumor suppressor mechanism, mediating removal of damaged or mutated cells from the cell-cycle pool, and may also contribute to the ageing process. In this study, we show that senescent human umbilical vein endothelial cells lose their ability to induce tissue factor (TF), a transmembrane protein with important roles in hemostasis and cancer progression, in response to thrombin or - independently of cell-surface receptors - phorbol-12-myristate-13-acetate. This phenomenon could not be explained by senescence-related alterations in the downstream signal transduction cascade or by accelerated TF mRNA degradation. Rather, using chromatin immuno-precipitation we could show that loss of TF gene inducibility during senescence occurs following chromatin remodelling of the TF promoter resulting from hypo-acetylation of histone H3. These findings were reversible after transduction of presenescent cultures with telomerase reverse transcriptase, enabling late-passage cultures to escape senescence. These results extend the involvement of heterochromatic gene silencing in senescence beyond cell cycle-related genes and suggest a novel anti-cancer mechanism of senescence through inhibition of TF inducibility.
authors.affiliation: Center for Molecular Cardiology, Institute of Physiology, University of Zurich, Switzerland; Cardiology, Triemli Hospital, Zurich, Switzerland. Electronic address: david.kurz@hispeed.ch.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kurz
authors.affiliation: Center for Molecular Cardiology, Institute of Physiology, University of Zurich, Switzerland.
authors.forename: Sravan
authors.initials: S
authors.lastname: Payeli
authors.affiliation: Center for Molecular Cardiology, Institute of Physiology, University of Zurich, Switzerland.
authors.forename: Helen
authors.initials: H
authors.lastname: Greutert
authors.affiliation: Center for Molecular Cardiology, Institute of Physiology, University of Zurich, Switzerland.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Briand Schumacher
authors.affiliation: Center for Molecular Cardiology, Institute of Physiology, University of Zurich, Switzerland; Cardiology, University Heart Center, University Hospital, Zurich, Switzerland.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.affiliation: Center for Molecular Cardiology, Institute of Physiology, University of Zurich, Switzerland; Cardiology, University Heart Center, University Hospital, Zurich, Switzerland.
authors.forename: Felix C
authors.initials: FC
authors.lastname: Tanner
mesh_terms: D000107:Acetylation; D016922:Cellular Senescence / Q000235:genetics*; D002843:Chromatin / Q000235:genetics; D044127:Epigenesis, Genetic; D015870:Gene Expression; D020868:Gene Silencing; D006487:Hemostasis; D006570:Heterochromatin / Q000235:genetics; D006657:Histones / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology*; D006801:Humans; D009369:Neoplasms; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D013925:Thromboplastin / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology
chemical_list: D002843:Chromatin; D006570:Heterochromatin; D006657:Histones; D012333:RNA, Messenger; D013925:Thromboplastin; D019098:Telomerase
keywords: Endothelium; Epigenetic regulation; Gene silencing; Senescence; Tissue factor