title: Poly(ADP-ribosyl)ation of Methyl CpG Binding Domain Protein 2 Regulates Chromatin Structure.
abstract: The epigenetic information encoded in the genomic DNA methylation pattern is translated by methylcytosine binding proteins like MeCP2 into chromatin topology and structure and gene activity states. We have shown previously that the MeCP2 level increases during differentiation and that it causes large-scale chromatin reorganization, which is disturbed by MeCP2 Rett syndrome mutations. Phosphorylation and other posttranslational modifications of MeCP2 have been described recently to modulate its function. Here we show poly(ADP-ribosyl)ation of endogenous MeCP2 in mouse brain tissue. Consequently, we found that MeCP2 induced aggregation of pericentric heterochromatin and that its chromatin accumulation was enhanced in poly(ADP-ribose) polymerase (PARP) 1(-/-) compared with wild-type cells. We mapped the poly(ADP-ribosyl)ation domains and engineered MeCP2 mutation constructs to further analyze potential effects on DNA binding affinity and large-scale chromatin remodeling. Single or double deletion of the poly(ADP-ribosyl)ated regions and PARP inhibition increased the heterochromatin clustering ability of MeCP2. Increased chromatin clustering may reflect increased binding affinity. In agreement with this hypothesis, we found that PARP-1 deficiency significantly increased the chromatin binding affinity of MeCP2 in vivo. These data provide novel mechanistic insights into the regulation of MeCP2-mediated, higher-order chromatin architecture and suggest therapeutic opportunities to manipulate MeCP2 function.
authors.affiliation: From the Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Becker
authors.affiliation: From the Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: From the Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Allmann
authors.affiliation: the Center for Integrated Protein Science at the Department of Biology, Ludwig Maximilians University Munich, 82152 Planegg-Martinsried, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Meilinger
authors.affiliation: From the Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Bertulat
authors.affiliation: From the Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Eck
authors.affiliation: the Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Hofstaetter
authors.affiliation: the Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland, and.
authors.forename: Giody
authors.initials: G
authors.lastname: Bartolomei
authors.affiliation: the Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland, and.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Hottiger
authors.affiliation: UMR7242 Biotechnology and Cell Signaling, Laboratory of Excellence Medalis, Strasbourg University, CNRS, Ecole Superieure de Biotechnologie de Strasbourg, BP10413, 67412 Illkirch Cedex, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Schreiber
authors.affiliation: the Center for Integrated Protein Science at the Department of Biology, Ludwig Maximilians University Munich, 82152 Planegg-Martinsried, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Leonhardt
authors.affiliation: From the Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany, cardoso@bio.tu-darmstadt.de.
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Cardoso
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D051381:Rats; D061987:Sf9 Cells; D018411:Spodoptera
chemical_list: D002843:Chromatin; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D011064:Poly Adenosine Diphosphate Ribose; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: 5-methylcytosine; DNA methylation; MeCP2; PARP-1; chromatin binding and organization; chromatin remodeling; heterochromatin; poly(ADP-ribosyl)ation; post-translational modification (PTM)