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

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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.

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Figure 1: Chromatin remodeling after CSDS in mice and in depressed humans.
Figure 2: Upstream regulators of Baz1a.
Figure 3: The ACF complex in NAc mediates stress susceptibility.
Figure 4: Regulation of ACF complex and nucleosome positioning genome-wide in NAc after CSDS.
Figure 5: Regulation of genes enriched in ACF-complex binding in NAc of susceptible mice.

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Acknowledgements

We thank the patients and their families for their contribution to the brain banks. This work was supported by the National Institute of Mental Health (grants P50 MH096890 and R01 MH51399) and the Hope for Depression Research Foundation. S.A. and P.V.-W. are funded by the Biotechnology and Biological Sciences Research Council (BBSRC).

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Authors and Affiliations

Authors

Contributions

H.S. and E.J.N. conceived the study and wrote the manuscript. H.S. performed most experiments with the help of D.M.D.-W., K.N.S., C.D., J.R., J.W.K., E.K., R.C.B., F.H.A., M.E.C., B.L., E.M., E.A.H., H.C., S.A.G., S.J.R., P.J.K., I.M. and D.M.D. N.-Y.S., S.A., P.V.-W. and L.S. conducted bioinformatics analysis. K.G., G.T. and C.T. provided post-mortem human brain samples. R.N. provided the HSV overexpression vectors. C.D.A. and P.V.-W. provided plasmid and antibody reagents.

Corresponding author

Correspondence to Eric J Nestler.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Discussion, Supplementary Figures 1–7, Supplementary Tables 1–3 and 7, Supplementary Notes and Supplementary References (PDF 1763 kb)

Supplementary Table 4

ACF complex–enriched loci in Nac (XLSX 54 kb)

Supplementary Table 5

Occupancy and shift events after CSDS (XLSX 2680 kb)

Supplementary Table 6

List of randomly generated genes that do not have ACF-complex enrichment in susceptible animals (XLSX 16 kb)

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Sun, H., Damez-Werno, D., Scobie, K. et al. ACF chromatin-remodeling complex mediates stress-induced depressive-like behavior. Nat Med 21, 1146–1153 (2015). https://doi.org/10.1038/nm.3939

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