Chronic cocaine-regulated epigenomic changes in mouse nucleus accumbens

Feng, Jian; Wilkinson, Matthew B.; Liu, Xiaochuan; Purushothaman, Immanuel; Ferguson, Deveroux; Vialou, Vincent; Maze, Ian; Shao, Ning‐Yi; Kennedy, Pamela J.; Koo, Ja Wook; Dias, Caroline; Laitman, Benjamin M.; Stockman, Victoria; LaPlant, Quincey; Cahill, Michael E.; Nestler, Eric J.; Shen, Li

doi:10.1186/gb-2014-15-4-r65

Cited by 163 publications

(206 citation statements)

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“…1,6 These neuroplastic changes appear to occur via alterations of transcripts and protein levels in intrinsic NAc neurons. [16][17][18][19] Similar to other psychostimulants, methamphetamine (METH) addiction is highly prevalent throughout the world and is associated with a diversity of neuropsychiatric signs and symptoms. 20 Some of the long-term effects of this drug may be the results of molecular events that occur in the rodent striatum and NAc after either contingent or noncontingent administration of the drug.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence

et al. 2016

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Epigenetic consequences of exposure to psychostimulants are substantial but the relationship of these changes to compulsive drug taking and abstinence is not clear. Here, we used a paradigm that helped to segregate rats that reduce or stop their methamphetamine (METH) intake (nonaddicted) from those that continue to take the drug compulsively (addicted) in the presence of footshocks. We used that model to investigate potential alterations in global DNA hydroxymethylation in the nucleus accumbens (NAc) because neuroplastic changes in the NAc may participate in the development and maintenance of drug-taking behaviors. We found that METH-addicted rats did indeed show differential DNA hydroxymethylation in comparison with both control and nonaddicted rats. Nonaddicted rats also showed differences from control rats. Differential DNA hydroxymethylation observed in addicted rats occurred mostly at intergenic sites located on long and short interspersed elements. Interestingly, differentially hydroxymethylated regions in genes encoding voltage (Kv1.1, Kv1.2, Kvb1 and Kv2.2)-and calcium (Kcnma1, Kcnn1 and Kcnn2)-gated potassium channels observed in the NAc of nonaddicted rats were accompanied by increased mRNA levels of these potassium channels when compared with mRNA expression in METH-addicted rats. These observations indicate that changes in differentially hydroxymethylated regions and increased expression of specific potassium channels in the NAc may promote abstinence from drug-taking behaviors. Thus, activation of specific subclasses of voltage-and/or calcium-gated potassium channels may provide an important approach to the beneficial treatment for METH addiction.

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Section: Introductionmentioning

confidence: 99%

Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence

et al. 2016

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“…Genome-wide methods have increasingly been used to obtain an unbiased view of chromatin changes in animal models of psychiatric disorders including changes in the NAc in addiction models (4,9,11). In nonneural tissues, H3R2me2a has been shown to act as a repressive mark that antagonizes H3K4me3 (17,18).…”

Section: Significancementioning

confidence: 99%

“…Important aspects of cocaine action appear to be mediated by changes in gene transcription via chromatin regulatory mechanisms such as histone acetylation or methylation on Lys (K) residues (3)(4)(5)(6)(7)(8)(9)(10)(11). However, in contrast to K methylation, the functional role of histone Arg (R) methylation remains underexplored in addiction models and poorly understood in the brain in general.…”

mentioning

confidence: 99%

“…The H3R2me2a mark is thought to be repressive in nature because of its ability to counteract the activator function of the nearby H3K4me3 mark (17,18). Our group has previously shown a pronounced enrichment of the H3K4me3 mark at key gene promoters in the NAc after repeated cocaine exposure (9). Based on these findings, we sought to determine whether PRMT6 and its associated histone mark, H3R2me2a, play roles in the remodeling of chromatin in the NAc after cocaine exposure.…”

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confidence: 99%

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Histone arginine methylation in cocaine action in the nucleus accumbens

Damez-Werno

Sun

Scobie

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanismssuch as histone acetylation and methylation on Lys residues-have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motivation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction.histone arginine (R) methylation | drug addiction | medium spiny neurons | ChIP-seq | Src R epeated cocaine exposure is marked by persistent changes in gene expression within the nucleus accumbens (NAc), a central component of the brain's reward circuitry (1, 2). Important aspects of cocaine action appear to be mediated by changes in gene transcription via chromatin regulatory mechanisms such as histone acetylation or methylation on Lys (K) residues (3-11). However, in contrast to K methylation, the functional role of histone Arg (R) methylation remains underexplored in addiction models and poorly understood in the brain in general.The methylation of R residues is catalyzed by the protein R methyltransferase (PRMT) family of enzymes, which can generate different methylated R states with diverse functional consequences, including monomethylarginine (MMA) and dimethylarginine (DMA) residues, the latter of which can be either asymmetric (aDMA) or symmetric (sDMA). PRMTs that catalyze aDMA are designated type I, and those that generate sDMA are designated type II (12, 13). Histone tails are prime targets for these PRMTs, and R methylation induces alterations in chromatin architecture, either condensing or relaxing its structure, thereby creating binding sites for regulatory proteins that contain specialized binding domains (14, 15).PRMT6, a nuclear enzyme that modifies histone tails, is the primary enzyme responsible for asymmetric dimethylation of R2 on histone H3 (H3R2me2a) in mammalian cells (14,16). The H3R2me2a mark is thought to be repressive in nature because of...

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“…Cocaine exposure can cause alterations in DNA methylation (Anier, Malinovskaja, Aonurm-Helm, Zharkovsky, & Kalda, 2010) and in chromatin enzymatic machinery, leading to changes in histone methylation, phosphorylation, and acetylation and changes the protein levels of histone deacetylases (HDACs) and the histone lysine methyltransferase G9a (Brami-Cherrier, Roze, Girault, Betuing, & Caboche, 2009;Feng et al, 2014;Maze et al, 2010).…”

Section: Cocaine Mitochondria and Epigeneticsmentioning

confidence: 99%