title: DPY30 regulates pathways in cellular senescence through ID protein expression.
abstract: Cellular senescence is an intrinsic defense mechanism to various cellular stresses: while still metabolically active, senescent cells stop dividing and enter a proliferation arrest. Here, we identify DPY30, a member of all mammalian histone H3K4 histone methyltransferases (HMTases), as a key regulator of the proliferation potential of human primary cells. Following depletion of DPY30, cells show a severe proliferation defect and display a senescent phenotype, including a flattened and enlarged morphology, elevated level of reactive oxygen species (ROS), increased SA-β-galactosidase activity, and formation of senescence-associated heterochromatin foci (SAHFs). While DPY30 depletion leads to a reduced level of H3K4me3-marked active chromatin, we observed a concomitant activation of CDK inhibitors, including p16INK4a, independent of H3K4me3. ChIP experiments show that key regulators of cell-cycle progression, including ID proteins, are under direct control of DPY30. Because ID proteins are negative regulators of the transcription factors ETS1/2, depletion of DPY30 leads to the transcriptional activation of p16INK4a by ETS1/2 and thus to a senescent-like phenotype. Ectoptic re-introduction of ID protein expression can partially rescue the senescence-like phenotype induced by DPY30 depletion. Thus, our data indicate that DPY30 controls proliferation by regulating ID proteins expression, which in turn lead to senescence bypass.
authors.affiliation: Centre for Genomic Regulation (CRG) and UPF, Department of Gene Regulation, Stem Cells and Cancer, Barcelona, Spain.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Simboeck
authors.forename: Arantxa
authors.initials: A
authors.lastname: Gutierrez
authors.forename: Luca
authors.initials: L
authors.lastname: Cozzuto
authors.forename: Malte
authors.initials: M
authors.lastname: Beringer
authors.forename: Livia
authors.initials: L
authors.lastname: Caizzi
authors.forename: William M
authors.initials: WM
authors.lastname: Keyes
authors.forename: Luciano
authors.initials: L
authors.lastname: Di Croce
mesh_terms: D015153:Blotting, Western; D016922:Cellular Senescence / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D003114:Colony-Forming Units Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism*; D046228:Microarray Analysis; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors; D001616:beta-Galactosidase
chemical_list: C507432:DPY30 protein, human; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D009687:Nuclear Proteins; D014157:Transcription Factors; D001616:beta-Galactosidase