title: Poly (ADP-ribose) glycohydrolase regulates retinoic acid receptor-mediated gene expression.
abstract: Poly-(ADP-ribose) glycohydrolase (PARG) is a catabolic enzyme that cleaves ADP-ribose polymers synthesized by poly-(ADP-ribose) polymerases. Here, transcriptome profiling and differentiation assay revealed a requirement of PARG for retinoic acid receptor (RAR)-mediated transcription. Mechanistically, PARG accumulates early at promoters of RAR-responsive genes upon retinoic acid treatment to promote the formation of an appropriate chromatin environment suitable for transcription. Silencing of PARG or knockout of its enzymatic activity maintains the H3K9me2 mark at the promoter of the RAR-dependent genes, leading to the absence of preinitiation complex formation. In the absence of PARG, we found that the H3K9 demethylase KDM4D/JMJD2D became PARsylated. Mutation of two glutamic acids located in the Jumonji N domain of KDM4D inhibited PARsylation. PARG becomes dispensable for ligand-dependent transcription when either a PARP inhibitor or a non-PARsylable KDM4D/JMJD2D mutant is used. Our results define PARG as a coactivator regulating chromatin remodeling during RA-dependent gene expression.
authors.affiliation: IGBMC, Department of Functional Genomics and Cancer, CNRS/INSERM/Université de Strasbourg, BP 163, 67404 Illkirch Cedex, CU Strasbourg, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Le May
authors.forename: Izarn
authors.initials: I
authors.lastname: Iltis
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Amé
authors.forename: Alexander
authors.initials: A
authors.lastname: Zhovmer
authors.forename: Denis
authors.initials: D
authors.lastname: Biard
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
authors.forename: Valérie
authors.initials: V
authors.lastname: Schreiber
authors.forename: Frédéric
authors.initials: F
authors.lastname: Coin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D042002:Chromatin Assembly and Disassembly; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D018698:Glutamic Acid; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000072482:Retinoic Acid Receptor alpha; C082925:retinoic acid receptor beta; D018698:Glutamic Acid; D014212:Tretinoin; D056484:Jumonji Domain-Containing Histone Demethylases; C521694:KDM4D protein, human; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase