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Nat Med. 2015 Oct;21(10):1146-53. doi: 10.1038/nm.3939. Epub 2015 Sep 21.

ACF chromatin-remodeling complex mediates stress-induced depressive-like behavior.

Author information

1
Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
2
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
3
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York, USA.
4
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
5
The Babraham Institute, Cambridge, UK.
6
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
7
Department of Psychology, University of California Los Angeles, Los Angeles, California, USA.
8
Department of Pharmacology and System Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
9
Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York, USA.
10
Institute on Addictions, University at Buffalo, Buffalo, New York, USA.
11
Department of Psychiatry, McGill University, Montreal, Québec, Canada.

Abstract

Improved treatment for major depressive disorder (MDD) remains elusive because of the limited understanding of its underlying biological mechanisms. It is likely that stress-induced maladaptive transcriptional regulation in limbic neural circuits contributes to the development of MDD, possibly through epigenetic factors that regulate chromatin structure. We establish that persistent upregulation of the ACF (ATP-utilizing chromatin assembly and remodeling factor) ATP-dependent chromatin-remodeling complex, occurring in the nucleus accumbens of stress-susceptible mice and depressed humans, is necessary for stress-induced depressive-like behaviors. We found that altered ACF binding after chronic stress was correlated with altered nucleosome positioning, particularly around the transcription start sites of affected genes. These alterations in ACF binding and nucleosome positioning were associated with repressed expression of genes implicated in susceptibility to stress. Together, our findings identify the ACF chromatin-remodeling complex as a critical component in the development of susceptibility to depression and in regulating stress-related behaviors.

PMID:
26390241
PMCID:
PMC4598281
DOI:
10.1038/nm.3939
[Indexed for MEDLINE]
Free PMC Article

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