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Nat Neurosci. 2014 Dec;17(12):1720-7. doi: 10.1038/nn.3871. Epub 2014 Oct 27.

Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors.

Author information

1
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
2
National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
3
1] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Pharmacology and System Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
4
1] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
5
Sigma Aldrich, Saint Louis, Missouri, USA.
6
Department of Pharmacology and System Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
7
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
8
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
9
Sangamo Biosciences Inc., Richmond, California.
10
McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

Abstract

Chronic exposure to drugs of abuse or stress regulates transcription factors, chromatin-modifying enzymes and histone post-translational modifications in discrete brain regions. Given the promiscuity of the enzymes involved, it has not yet been possible to obtain direct causal evidence to implicate the regulation of transcription and consequent behavioral plasticity by chromatin remodeling that occurs at a single gene. We investigated the mechanism linking chromatin dynamics to neurobiological phenomena by applying engineered transcription factors to selectively modify chromatin at a specific mouse gene in vivo. We found that histone methylation or acetylation at the Fosb locus in nucleus accumbens, a brain reward region, was sufficient to control drug- and stress-evoked transcriptional and behavioral responses via interactions with the endogenous transcriptional machinery. This approach allowed us to relate the epigenetic landscape at a given gene directly to regulation of its expression and to its subsequent effects on reward behavior.

PMID:
25347353
PMCID:
PMC4241193
DOI:
10.1038/nn.3871
[Indexed for MEDLINE]
Free PMC Article

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