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. 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 ΔFosB. Using conditional mutagenesis and viral-mediated gene transfer, we found that G9a downregulation increased dendritic spine plasticity of nucleus accumbens neurons and enhanced preference for cocaine, thereby establishing a crucial role for histone methylation in the long-term actions of cocaine.Repeated cocaine exposure is characterized by persistent changes in gene expression and altered neuronal morphology within the nucleus accumbens (NAc), a key component of the brain's reward circuitry (1-2). Chromatin remodeling is important in aberrant transcriptional changes in this brain region that may underlie aspects of cocaine addiction (3-9). Cocaine regulation of chromatin structure in the NAc results, in part, from direct cocaine-induced modifications of the chromatin enzymatic machinery, leading to changes in histone acetylation *To whom correspondence should be addressed. eric.nestler@mssm.edu. I certify that none of the materials included within the manuscript entitled Essential Role of the Histone Methyltransferase G9a in Cocaineinduced Plasticity have been previously published or are under consideration elsewhere, including on the Internet.All work involving the use of animals was conducted in accordance with institutional and IACUC guidelines at both The

Mutation of MeCP2 alters transcriptional regulation of select immediate-early genes

“…7 The psychostimulants amphetamine and cocaine drive long-lasting changes in the function of brain reward circuits by inducing the transcription of new gene products. 18,19 Psychostimulant-regulated immediate-early genes (IEGs) include both transcription factors of the Fos/Jun/Egr families as well neuronally-enriched genes such as Arc, Bdnf and Cdk5 that play direct roles in the plasticity of synaptic strength and structure. [19][20][21][22] We have shown that amphetamine increases expression of Fos/ Jun family transcription factors in the striatum of both WT and MUT mice of the Mecp2 308 strain, demonstrating that expression of wild-type MeCP2 is not required for the IEG response.…”

“…18,19 Psychostimulant-regulated immediate-early genes (IEGs) include both transcription factors of the Fos/Jun/Egr families as well neuronally-enriched genes such as Arc, Bdnf and Cdk5 that play direct roles in the plasticity of synaptic strength and structure. [19][20][21][22] We have shown that amphetamine increases expression of Fos/ Jun family transcription factors in the striatum of both WT and MUT mice of the Mecp2 308 strain, demonstrating that expression of wild-type MeCP2 is not required for the IEG response. 7 However, both the magnitude of FosB and JunB induction following a single dose of amphetamine and the plasticity of Fos, FosB and JunB inducibility following repeated amphetamine is significantly altered in Mecp2 MUT mice.…”

“…Importantly both of these drugs increase extracellular dopamine levels in the striatum and both are known to induce striatal IEG expression. 7,19,26 To determine whether the Mecp2 308 mutation affects neural processes that are common to the actions of both amphetamine and cocaine, we first monitored the locomotor response of Mecp2 WT and MUT mice to administration of a single dose of 20 mg/kg cocaine (i.p.) in the open field (Fig.…”

Essential roles of the histone methyltransferase ESET in the epigenetic control of neural progenitor cells during development

“…RESEARCH ARTICLE ESET in neural development Epigenetic regulation in the nervous system Recent studies revealed that epigenetic regulation is essential for the maintenance of neuronal identity. Ablation of the H3K9 methyltransferase G9a (Ehmt2 -Mouse Genome Informatics), which catalyzes dimethylation of H3K9 (Tachibana et al, 2001), leads to derepression of non-neuronal genes and NPC-specific genes in neurons and to abnormal behaviors in mice (Schaefer et al, 2009;Maze et al, 2010). The precise role of ESET in neurons is not known, but it was shown that overexpression of ESET in neurons leads to the repression of some neuronal genes and to abnormal behaviors in mice, and that ESET expression is highly upregulated in patients with Huntington's disease (Ryu et al, 2006;Jiang et al, 2010).…”

Development of Novel Pharmacotherapeutics for Tobacco Dependence: Progress and Future Directions

“…In particular, it is now well established that chromatin remodeling is a major genomic response to cocaine exposure that can alter the subsequent motivational properties of the drug (Borrelli, Nestler, Allis, & Sassone-Corsi, 2008;Renthal & Nestler, 2008). Indeed, proteins involved in epigenetic processes, including histone acetylation (HDACs) (Kumar et al, 2005;Renthal et al, 2007), deacetylation (SIRT1) (Renthal et al, 2009), methylation (G9a) (Maze et al, 2010), DNA methylation (DNMT1 and 3A, 3B) , methyl CpG binding proteins (MeCP2) , and microRNAs including miR-212 and miR-132 Im et al, 2010;Schaefer et al, 2010), all play essential roles in regulating cocaine reward and cocainetaking behaviors. However, very little is known concerning the roles for this epigenetic machinery in the reinforcing properties of nicotine, or if targeting this machinery is a viable approach to developing new products for smoking cessation.…”