title: Cocaine represses protein phosphatase-1Cβ through DNA methylation and Methyl-CpG Binding Protein-2 recruitment in adult rat brain.
abstract: Repeated cocaine exposure induces epigenetic factors such as DNA methyl-binding proteins, indicating that resulting changes in gene expression are mediated by alterations in brain DNA methylation. While the activity of protein phosphatase type-1 (PP1) is involved in cocaine effects and in brain plasticity, the expression of the PP1Cβ catalytic subunit gene was identified here as modulated by cocaine. Its expression was induced together with that of PP1Cγ in the brain of Methyl-CpG Binding Protein-2 (Mecp2) mutant mice, whereas PP1Cα expression was not affected, illustrating a different regulation of PP1C isoforms. Repeated cocaine administration was found to increase DNA methylation at the PP1Cβ gene together with its binding to Mecp2 in rat caudate putamen, establishing a link between two genes involved in cocaine-related effects and in learning and memory processes. Cocaine also increased DNMT3 expression, resulting in PP1Cβ repression that did not occur in the presence of DNMT inhibitor. Cocaine-induced PP1Cβ repression was observed in several brain structures, as evaluated by RT-qPCR, immunohistochemistry and Western blot, but did not occur after a single cocaine injection. Our data demonstrate that PP1Cβ is a direct MeCP2-target gene in vivo. They suggest that its repression may participate to behavioral adaptations triggered by the drug.
authors.affiliation: Laboratoire de Neurosciences Cognitives et Adaptatives, UMR 7364 CNRS, Université de Strasbourg, 67000 Strasbourg, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pol Bodetto
authors.forename: Delphine
authors.initials: D
authors.lastname: Carouge
authors.forename: Mathieu
authors.initials: M
authors.lastname: Fonteneau
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Dietrich
authors.forename: Jean
authors.initials: J
authors.lastname: Zwiller
authors.forename: Patrick
authors.initials: P
authors.lastname: Anglard
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002421:Caudate Nucleus / Q000187:drug effects* / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis; D019175:DNA Methylation / Q000187:drug effects*; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D008297:Male; D009154:Mutation; D054645:Protein Phosphatase 1 / Q000096:biosynthesis*; D021122:Protein Subunits / Q000096:biosynthesis; D011699:Putamen / Q000187:drug effects / Q000378:metabolism*; D051381:Rats
chemical_list: D004268:DNA-Binding Proteins; C115368:MBD2 protein; D021122:Protein Subunits; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D054645:Protein Phosphatase 1; D003042:Cocaine
keywords: 5-Aza-2′-deoxycytidine; 5-dAZA; 5-hmC; 5-hydroxymethylcytosine; 5-mC; 5-methylcytosine; CGI; CPP; CPu; CREB; ChIP; Cocaine; CpG Island; DARPP-32; DNA methylation; DNA methyltransferase; DNMT; Drugs of abuse; Epigenetics; MBD; MeCP2; MeDIP; Mecp2; Methyl-CpG Binding Protein-2; Methyl-CpG Binding Proteins; NAc; PFCx; PKA; PP1C; Protein phosphatase-1; RT-qPCR; Rett syndrome; cAMP response element-binding protein; cAMP-dependent protein kinase; caudate putamen; chromatin immunoprecipitation; conditioned place preference; dopamine- and cyclic AMP-regulated phosphoprotein-32; methylated DNA immunoprecipitation; nucleus accumbens; prefrontal cortex; protein phosphatase type-1 catalytic subunit; reverse transcription-quantitative PCR