Essential Role of the Histone Methyltransferase G9a in Cocaine-Induced Plasticity

Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA.
Science (Impact Factor: 33.61). 01/2010; 327(5962):213-6. DOI: 10.1126/science.1179438
Source: PubMed


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 ∆FosB. 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.

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    • "Recent studies of the mechanisms of learning and memory indicate that active regulation of gene expression is necessary for experience-triggered lasting functional plasticity (Zovkic and Sweatt, 2012), which also supports mechanisms of longlasting addictive behaviors. The role of epigenetic mechanisms is involved in various types of neuronal plasticity and behavioral disorders, such as long-term behavior in maternal caring (Weaver et al., 2004; Meaney and Szyf, 2005), memory formation and maintenance (Levenson and Sweatt, 2005; Lubin et al., 2008; Roth and Sweatt, 2009; Day and Sweatt, 2010; Johnson et al., 2012), as well as the development of addictive behavior (Marutha Ravindran and Ticku, 2004; Pandey et al., 2008; Malvaez et al., 2009; Maze et al., 2010; Wong et al., 2011; Moonat et al., 2013; Warnault et al., 2013). "
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    ABSTRACT: Repeated alcohol-exposure is known to increase subsequent ethanol consumption in mice. However, the underlying mechanisms have not been fully elucidated. One postulated mechanism involves epigenetic modifications including histone modifications and DNA methylationof relevant genes such as NR2B or BDNF. To investigate the role of epigenetic mechanisms in the development of alcohol drinking behavior, an established chronic intermittent ethanol (CIE) exposure reinforced ethanol drinking mouse model with vapor inhalation over two 9-day treatment regimens was used. The DNA methyltransferase inhibitor, 5-azacytidine (5'AZA) or the histone deacetylase inhibitor, Trichostatin A (TSA) was administered (i.p.) to C57BL/6 mice 30 min before daily exposure to CIE. Changes in ethanol consumption were measured using the two bottle choice test. The results indicated that systemic administration of TSA (2.5 µg/g) facilitated CIE-induced ethanol drinking, but systemic administration of 5administration ofAZA (2µg/g) did not cause the same effect. However, when 5'AZA was administered by intracerebroventricular injection, it facilitated CIE-induced ethanol drinking. Furthermore, the increased drinking caused by CIE was prevented by injection of a methyl donor, S-adenosyl-L-methionine. To provide evidence that CIE- or TSA-induced DNA demethylation and histone modifications ofthe NR2B promoter may underlie the altered ethanol consumption, we examined epigenetic modifications and NR2B expression in the prefrontal cortex of these mice. CIE or TSA decreased DNA methylation and increased histone acetylation in the NR2B gene promoter, as well as mRNAlevels of NR2B in these mice. Taken together, these results indicate that epigenetic modifications are involved in regulating ethanol drinking behavior, partiallythroughaltering NR2B expression. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    Full-text · Article · Oct 2014 · The International Journal of Neuropsychopharmacology
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    • "To understand the behavioral importance of MBII-52 downregulation in NAc after repeated cocaine exposure or cocaine-induced CPP, mice were received intra-NAc injections of lentiviruses expressing MBII-52 (LV-MBII-52) to temporally and specifically overexpress MBII-52 in the NAc (Fig. 3A), and then evaluated whether such genetic manipulation could block cocaine-induced CPP, which provides an indirect measure of cocaine reward [18], [19]. Importantly, MBII-52 overexpression in this brain region markedly attenuated the preference for cocaine in comparison to that seen in animals expressing GFP (Fig. 3B). "
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    ABSTRACT: Cocaine dependence involves in the brain's reward circuit as well as nucleus accumbens (NAc), a key region of the mesolimbic dopamine pathway. Many studies have documented altered expression of genes and identified transcription factor networks and epigenetic processes that are fundamental to cocaine addiction. However, all these investigations have focused on mRNA and/or miRNA, which may not reflect the involvement of small nucleolar RNAs (snoRNAs), which has been implied in a broad range of biological processes and complex diseases including brain development and neuropathologocal process. To further address the role of snoRNA in cocaine addiction, we show that repeated exposure and conditioned place preference (CPP) training to cocaine negatively regulates the expression of MBII-52 mRNA level, which is a brain-specific C/D box snoRNA, but not influences the serotonin receptor 2C (5HT2CR) mRNA level in NAc. Furthemore, we show, developing lentiviral vector (LV)-expressing MBII-52 and LV-5HT2CR for stable and regulatable MBII-52 and LV-5HT2CR expression. LV-MBII-52 and LV-5HT2CR expression in NAc attenuate cocaine induced CPP and locomotor activity. Taken together, these findings show that MBII-52 and 5HT2CR exert an inhibitory influence on the behavioral responses to cocaine exposure.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "Drugs of abuse such as cocaine have been shown to alter the expression levels of several histone- and DNA-modifying enzymes within key brain reward regions, such as the nucleus accumbens (NAc) [7-10]. Importantly, these enzyme changes, which include altered levels of certain histone deacetylases and histone lysine methyltransferases, are associated with cocaine-induced changes in histone acetylation or lysine methylation at many specific candidate genes, which are already known to be involved in cocaine action [9,11]. Recently, cross-talk has been demonstrated between regulation of histone acetylation and lysine methylation in NAc [12]. "
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    ABSTRACT: Increasing evidence supports a role for altered gene expression in mediating the lasting effects of cocaine on the brain, and recent work has demonstrated the involvement of chromatin modifications in these alterations. However, all such studies to date have been restricted by their reliance on microarray technologies that have intrinsic limitations. We use next generation sequencing methods, RNA-seq and ChIP-seq for RNA polymerase II and several histone methylation marks, to obtain a more complete view of cocaine-induced changes in gene expression and associated adaptations in numerous modes of chromatin regulation in the mouse nucleus accumbens, a key brain reward region. We demonstrate an unexpectedly large number of pre-mRNA splicing alterations in response to repeated cocaine treatment. In addition, we identify combinations of chromatin changes, or signatures, that correlate with cocaine-dependent regulation of gene expression, including those involving pre-mRNA alternative splicing. Through bioinformatic prediction and biological validation, we identify one particular splicing factor, A2BP1(Rbfox1/Fox-1), which is enriched at genes that display certain chromatin signatures and contributes to drug-induced behavioral abnormalities. Together, this delineation of the cocaine-induced epigenome in the nucleus accumbens reveals several novel modes of regulation by which cocaine alters the brain. We establish combinatorial chromatin and transcriptional profiles in mouse nucleus accumbens after repeated cocaine treatment. These results serve as an important resource for the field and provide a template for the analysis of other systems to reveal new transcriptional and epigenetic mechanisms of neuronal regulation.
    Full-text · Article · Apr 2014 · Genome biology
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