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Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9623-8. doi: 10.1073/pnas.1605045113. Epub 2016 Aug 9.

Histone arginine methylation in cocaine action in the nucleus accumbens.

Author information

1
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
2
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065;
3
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21230;
4
Department of Pharmacology and Toxicology, State University of New York, Buffalo, NY 14214;
5
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065;
6
Institute of Molecular and Cell Biology, Singapore, SGP 138673;
7
Douglas Mental Health Institute, McGill University, Montréal, QC, Canada H4H 1R3;
8
Department of Neuroscience, University of Torino, 10126 Torino, Italy;
9
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139.
10
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; eric.nestler@mssm.edu.

Abstract

Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms-such 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.

KEYWORDS:

ChIP-seq; Src; drug addiction; histone arginine (R) methylation; medium spiny neurons

PMID:
27506785
PMCID:
PMC5003250
DOI:
10.1073/pnas.1605045113
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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