Epigenetic Regulation of Cellular Senescence by WNT-MYC-Polycomb Signaling Ito, Takahiro creator 2016 xviii, 158 p. born digital Thesis (Ph.D.)--Brown University, 2016 Sedivy, John Director Helfand, Stephen Reader Chen, Qian Reader Fairbrother, William Reader Shi, Yang Reader Brown University. BIOMED: Molecular Biology, Cell Biology, and Biochemistry sponsor theses Polycomb Group (PcG) epigenetic regulators are important but not well-understood components of cellular senescence. EZH2, a PcG histone H3 lysine-27 methyltransferase, is repressed in senescent cells and activated in many tumours. We show that repression of EZH2 promotes senescence through two independent mechanisms. First, downregulation of EZH2 in proliferating cells initiates a rapid DNA damage response prior to depletion of H3K27me3 marks. Second, reduction of EZH2 activity causes a gradual loss of H3K27me3 that induces p16 (CDKN2A) expression and contributes to the activation of the senescence-associated secretory phenotype. Repression of EZH2 is mediated by WNT and MYC signaling, and EZH2 is required for senescence induced by WNT2 or MYC depletion. These mechanisms elucidate how PcG-mediated epigenetic changes are involved in the regulation of cellular senescence, suggest new therapeutic targets downstream of WNT and MYC in the context of cancer, and provide insights on the generation of senescent cells during aging. Aging Cellular Senescence Epigenetics RPB 20170531 10.7301/Z0DN43HTIn CopyrightCollection is open for research.dissertations