Histone arginine methylation in cocaine action in the nucleus accumbens
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Author(s)
Damez-Werno, Diane M.
Sun, HaoSheng
Scobie, Kimberly N.
Shao, Ningyi
Rabkin, Jaclyn
Dias, Caroline
Calipari, Erin S.
Maze, Ian
Pena, Catherine J.
Walker, Deena M.
Date Issued
August 2016
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Damez-Werno, Diane M. et al. “Histone Arginine Methylation in Cocaine Action in the Nucleus Accumbens.” Proceedings of the National Academy of Sciences 113, 34 (August 2016): 9623–9628 © 2016 National Academy of Sciences
Version
Final published version
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 motiv ation 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: histone arginine (R) methylation; drug addiction; medium spiny neurons; ChIP-seq; Src
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
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DOI of Published Version
https://doi.org/10.1073/pnas.1605045113
