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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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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).

Author information

Author notes

    • Diane M Damez-Werno
    • , Kimberly N Scobie
    •  & Ning-Yi Shao

    These authors contributed equally to this work.

Affiliations

  1. Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • HaoSheng Sun
    • , Diane M Damez-Werno
    • , Kimberly N Scobie
    • , Ning-Yi Shao
    • , Caroline Dias
    • , Jacqui Rabkin
    • , Ja Wook Koo
    • , Rosemary C Bagot
    • , Francisca H Ahn
    • , Michael E Cahill
    • , Benoit Labonté
    • , Ezekiell Mouzon
    • , Elizabeth A Heller
    • , Hannah Cates
    • , Sam A Golden
    • , Scott J Russo
    • , Ian Maze
    • , Li Shen
    •  & Eric J Nestler
  2. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • HaoSheng Sun
    • , Diane M Damez-Werno
    • , Kimberly N Scobie
    • , Ning-Yi Shao
    • , Caroline Dias
    • , Jacqui Rabkin
    • , Ja Wook Koo
    • , Rosemary C Bagot
    • , Francisca H Ahn
    • , Michael E Cahill
    • , Benoit Labonté
    • , Ezekiell Mouzon
    • , Elizabeth A Heller
    • , Hannah Cates
    • , Sam A Golden
    • , Scott J Russo
    • , Ian Maze
    • , Li Shen
    •  & Eric J Nestler
  3. Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York, USA.

    • Erica Korb
    • , Ian Maze
    •  & C David Allis
  4. Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Kelly Gleason
    •  & Carol Tamminga
  5. The Babraham Institute, Cambridge, UK.

    • Simon Andrews
    •  & Patrick Varga-Weisz
  6. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Rachael Neve
  7. Department of Psychology, University of California Los Angeles, Los Angeles, California, USA.

    • Pamela J Kennedy
  8. Department of Pharmacology and System Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ian Maze
  9. Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York, USA.

    • David M Dietz
  10. Institute on Addictions, University at Buffalo, Buffalo, New York, USA.

    • David M Dietz
  11. Department of Psychiatry, McGill University, Montreal, Québec, Canada.

    • Gustavo Turecki

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Eric J Nestler.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Discussion, Supplementary Figures 1–7, Supplementary Tables 1–3 and 7, Supplementary Notes and Supplementary References

Excel files

  1. 1.

    Supplementary Table 4

    ACF complex–enriched loci in Nac

  2. 2.

    Supplementary Table 5

    Occupancy and shift events after CSDS

  3. 3.

    Supplementary Table 6

    List of randomly generated genes that do not have ACF-complex enrichment in susceptible animals

About this article

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DOI

https://doi.org/10.1038/nm.3939

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