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

TitleACF chromatin-remodeling complex mediates stress-induced depressive-like behavior.
Publication TypeJournal Article
Year of Publication2015
AuthorsSun H, Damez-Werno DM, Scobie KN, Shao N-Y, Dias C, Rabkin J, Koo JWook, Korb E, Bagot RC, Ahn FH, Cahill ME, Labonte B, Mouzon E, Heller EA, Cates H, Golden SA, Gleason K, Russo SJ, Andrews S, Neve R, Kennedy PJ, Maze I, Dietz DM, C Allis D, Turecki G, Varga-Weisz P, Tamminga C, Shen L, Nestler EJ
JournalNat Med
Volume21
Issue10
Pagination1146-53
Date Published2015 Oct
ISSN1546-170X
KeywordsAnimals, Chromatin Assembly and Disassembly, Depression, Humans, Male, Mice, Mice, Inbred C57BL, Stress, Psychological, Transcription Factors
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.

DOI10.1038/nm.3939
Alternate JournalNat. Med.
PubMed ID26390241
PubMed Central IDPMC4598281
Grant ListBBS/E/B/0000H125 / / Biotechnology and Biological Sciences Research Council / United Kingdom
/ / Biotechnology and Biological Sciences Research Council / United Kingdom
R01 MH51399 / MH / NIMH NIH HHS / United States
P50 MH096890 / MH / NIMH NIH HHS / United States
R01 MH051399 / MH / NIMH NIH HHS / United States

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