Histone arginine methylation in cocaine action in the nucleus accumbens

Abstract

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...

Epigenetic Signaling in Psychiatric Disorders

“…Chronic cocaine alters histone phosphorylation 154; 155 and arginine methylation 156 . A recent paper established a critical role for poly(ADP-ribosyl)ation.…”

“…Chromatin remodeling likely contributes to cocaine-induced expansion of euchromatin. Recent work suggests that cocaine, like chronic social defeat, regulates the expression of the ISWI family of chromatin remodelers and that this upregulation may be important for altered nucleosome spacing 156 .…”

Prefrontal cortex expression of chromatin modifier genes in male WSP and WSR mice changes across ethanol dependence, withdrawal, and abstinence

“…PRMT1 was found to be downregulated in the nucleus accumbens of mice repeatedly exposed to cocaine and was implicated in the behavioral response to cocaine (Li et al, 2015). PRMT6 was found to be downregulated in the nucleus accumbens medium spiny neurons expressing dopamine D2 receptors after repeated cocaine exposures; this effect was implicated in the protection against cocaine-induced addictive-like behavioral abnormalities (Damez-Werno et al, 2016). Together these studies support a role for PRTMs in drug addiction, including, perhaps, alcoholism.…”

Invited Commentary: In a Genomic Era, Should We Promote Dopamine Homeostasis to Treat Opiate/ Opioid Abuse, Instead of Blocking Brain Dopamine Function?

“…Thousands of published studies involve these reward genes and pathways, influencing the function of these neurotransmitters. This research has involved the identification of gene (DNA) variations or alleles that individuals are born with as well as epigenetic (environmental RNA) changes that may alter the healthy, intended function of DNA (Damez-Werno et al, 2016). In simpler terms, Nestler's group showed that if histone arginine methylation is blocked on the dopamine D2 receptor gene following cocaine-induced epigenetics, the resultant dopamine signaling at the reward site [Nucleus Accumbens (Nac)] functions as a homeostatic brake to restrain cocaine action.…”