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

• Published in: Nature medicine Vol. 21; no. 10; pp. 1146 - 1153
• Main Authors: Sun, HaoSheng, Damez-Werno, Diane M, Scobie, Kimberly N, Shao, Ning-Yi, Dias, Caroline, Rabkin, Jacqui, Koo, Ja Wook, Korb, Erica, Bagot, Rosemary C, Ahn, Francisca H, Cahill, Michael E, Labonté, Benoit, Mouzon, Ezekiell, Heller, Elizabeth A, Cates, Hannah, Golden, Sam A, Gleason, Kelly, Russo, Scott J, Andrews, Simon, Neve, Rachael, Kennedy, Pamela J, Maze, Ian, Dietz, David M, Allis, C David, Turecki, Gustavo, Varga-Weisz, Patrick, Tamminga, Carol, Shen, Li, Nestler, Eric J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-10-2015; Nature Publishing Group
• Subjects: 38; 45/15; 631/378/1689/1414; 64; 64/60; 692/699/476/1414; Animals; ATP; Biomedicine; Brain; Cancer Research; Chromatin; Chromatin Assembly and Disassembly; Chromosomal Proteins, Non-Histone; Depression - metabolism; Depression, Mental; Epigenetics; Genetic aspects; Humans; Infectious Diseases; Male; Mental depression; Metabolic Diseases; Mice; Mice, Inbred C57BL; Molecular Medicine; Neurosciences; Physiological aspects; Risk factors; Stress; Stress, Psychological; Transcription Factors - genetics; Transcription Factors - physiology; Canada; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3939

Upregulation of the ATP-dependent ACF chromatin-remodeling complex in the NAc is a necessary and causal component for susceptibility to stress-induced depressive behaviors in mice, and this complex is also shown to be upregulated in the NAc of depressed humans.
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.