title: Histone arginine methylation in cocaine action in the nucleus accumbens.
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.
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Diane M
authors: 0000-0001-6875-9257
authors: DM
authors: Damez-Werno
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: HaoSheng
authors: H
authors: Sun
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Kimberly N
authors: KN
authors: Scobie
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Ningyi
authors: N
authors: Shao
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Jaclyn
authors: J
authors: Rabkin
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Caroline
authors: C
authors: Dias
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Erin S
authors: ES
authors: Calipari
authors: 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;
authors: Ian
authors: I
authors: Maze
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Catherine J
authors: CJ
authors: Pena
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Deena M
authors: DM
authors: Walker
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Michael E
authors: ME
authors: Cahill
authors: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21230;
authors: Ramesh
authors: R
authors: Chandra
authors: Department of Pharmacology and Toxicology, State University of New York, Buffalo, NY 14214;
authors: Amy
authors: A
authors: Gancarz
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Ezekiell
authors: 0000-0003-0084-0897
authors: E
authors: Mouzon
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Joseph A
authors: JA
authors: Landry
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Hannah
authors: H
authors: Cates
authors: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21230;
authors: Mary-Kay
authors: MK
authors: Lobo
authors: Department of Pharmacology and Toxicology, State University of New York, Buffalo, NY 14214;
authors: David
authors: D
authors: Dietz
authors: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065;
authors: C David
authors: CD
authors: Allis
authors: Institute of Molecular and Cell Biology, Singapore, SGP 138673;
authors: Ernesto
authors: E
authors: Guccione
authors: Douglas Mental Health Institute, McGill University, Montréal, QC, Canada H4H 1R3;
authors: Gustavo
authors: G
authors: Turecki
authors: Department of Neuroscience, University of Torino, 10126 Torino, Italy;
authors: Paola
authors: P
authors: Defilippi
authors: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors: Rachael L
authors: RL
authors: Neve
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Yasmin L
authors: YL
authors: Hurd
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Li
authors: L
authors: Shen
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; eric.nestler@mssm.edu.
authors: Eric J
authors: EJ
authors: Nestler
mesh_terms: D000107:Acetylation; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009714:Nucleus Accumbens / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D006657:Histones; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C000621587:p140cap protein, mouse; C577312:PRMT6 protein, mouse; D011484:Protein-Arginine N-Methyltransferases; D003042:Cocaine
keywords: ChIP-seq; Src; drug addiction; histone arginine (R) methylation; medium spiny neurons