title: Essential role of the histone methyltransferase G9a in cocaine-induced plasticity.
abstract: Cocaine-induced alterations in gene expression cause changes in neuronal morphology and behavior that may underlie cocaine addiction. In mice, we identified an essential role for histone 3 lysine 9 (H3K9) dimethylation and the lysine dimethyltransferase G9a in cocaine-induced structural and behavioral plasticity. Repeated cocaine administration reduced global levels of H3K9 dimethylation in the nucleus accumbens. This reduction in histone methylation was mediated through the repression of G9a in this brain region, which was regulated by the cocaine-induced transcription factor DeltaFosB. Using conditional mutagenesis and viral-mediated gene transfer, we found that G9a down-regulation increased the dendritic spine plasticity of nucleus accumbens neurons and enhanced the preference for cocaine, thereby establishing a crucial role for histone methylation in the long-term actions of cocaine.
authors.affiliation: Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Maze
authors.forename: Herbert E
authors.initials: HE
authors.lastname: Covington
authors.forename: David M
authors.initials: DM
authors.lastname: Dietz
authors.forename: Quincey
authors.initials: Q
authors.lastname: LaPlant
authors.forename: William
authors.initials: W
authors.lastname: Renthal
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
authors.forename: Max
authors.initials: M
authors.lastname: Mechanic
authors.forename: Ezekiell
authors.initials: E
authors.lastname: Mouzon
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Ren
authors.forename: Srihari C
authors.initials: SC
authors.lastname: Sampath
authors.forename: Yasmin L
authors.initials: YL
authors.lastname: Hurd
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.forename: Alexander
authors.initials: A
authors.lastname: Tarakhovsky
authors.forename: Anne
authors.initials: A
authors.lastname: Schaefer
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000008:administration & dosage* / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000209:etiology / Q000378:metabolism; D049229:Dendritic Spines / Q000502:physiology; D015536:Down-Regulation; D004794:Enzyme Repression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012201:Reward; D012646:Self Administration; D014158:Transcription, Genetic
chemical_list: C483819:Fosb protein, mouse; D006657:Histones; D016760:Proto-Oncogene Proteins c-fos; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D003042:Cocaine; D008239:Lysine