title: Conserved antagonism between JMJD2A/KDM4A and HP1γ during cell cycle progression.
abstract: The KDM4/JMJD2 family of histone demethylases is amplified in human cancers. However, little is known about their physiologic or tumorigenic roles. We have identified a conserved and unappreciated role for the JMJD2A/KDM4A H3K9/36 tridemethylase in cell cycle progression. We demonstrate that JMJD2A protein levels are regulated in a cell cycle-dependent manner and that JMJD2A overexpression increased chromatin accessibility, S phase progression, and altered replication timing of specific genomic loci. These phenotypes depended on JMJD2A enzymatic activity. Strikingly, depletion of the only C. elegans homolog, JMJD-2, slowed DNA replication and increased ATR/p53-dependent apoptosis. Importantly, overexpression of HP1γ antagonized JMJD2A-dependent progression through S phase, and depletion of HPL-2 rescued the DNA replication-related phenotypes in jmjd-2(-/-) animals. Our findings describe a highly conserved model whereby JMJD2A regulates DNA replication by antagonizing HP1γ and controlling chromatin accessibility.
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, 13th Street, Charlestown, MA 02129, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Black
authors.forename: Andrew
authors.initials: A
authors.lastname: Allen
authors.forename: Capucine
authors.initials: C
authors.lastname: Van Rechem
authors.forename: Emily
authors.initials: E
authors.lastname: Forbes
authors.forename: Michelle
authors.initials: M
authors.lastname: Longworth
authors.forename: Katrin
authors.initials: K
authors.lastname: Tschöp
authors.forename: Claire
authors.initials: C
authors.lastname: Rinehart
authors.forename: Jonathan
authors.initials: J
authors.lastname: Quiton
authors.forename: Ryan
authors.initials: R
authors.lastname: Walsh
authors.forename: Andrea
authors.initials: A
authors.lastname: Smallwood
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Dyson
authors.forename: Johnathan R
authors.initials: JR
authors.lastname: Whetstine
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014162:Transfection
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human