Histone arginine methylation in cocaine action in the nucleus accumbens
| Autor: | Diane M. Damez-Werno, Caroline Dias, Rachael L. Neve, Ning-Yi Shao, Gustavo Turecki, Jaclyn Rabkin, Mary Kay Lobo, Yasmin L. Hurd, C. David Allis, Ernesto Guccione, Ian Maze, Michael E. Cahill, David M. Dietz, Hannah M. Cates, Amy M. Gancarz, Ezekiell Mouzon, Joseph A. Landry, HaoSheng Sun, Ramesh Chandra, Catherine Jensen Pena, Kimberly N. Scobie, Eric J. Nestler, Paola Defilippi, Deena M. Walker, Erin S. Calipari, Li Shen |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Protein-Arginine N-Methyltransferases Epigenetics of cocaine addiction Nucleus accumbens Biology Pharmacology Medium spiny neuron Methylation Nucleus Accumbens Histones Rats Sprague-Dawley Cocaine-Related Disorders Mice 03 medical and health sciences Histone H3 0302 clinical medicine Cocaine Histone arginine methylation Transcriptional regulation Drug addiction Animals Humans Epigenetics Histone arginine (R) methylation Medium spiny neurons Neurons Multidisciplinary Receptors Dopamine D2 Receptors Dopamine D1 Acetylation ChIP-seq Src Biological Sciences Molecular biology Rats Mice Inbred C57BL 030104 developmental biology Histone biology.protein Carrier Proteins Protein Processing Post-Translational 030217 neurology & neurosurgery |
| Zdroj: | Proceedings of the National Academy of Sciences. 113:9623-9628 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1605045113 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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