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Neuronal activity modifies the chromatin accessibility landscape in the adult brain

Nature Neuroscience volume 20, pages 476483 (2017) | Download Citation

Abstract

Neuronal activity-induced gene expression modulates the function and plasticity of the nervous system. It is unknown whether and to what extent neuronal activity may trigger changes in chromatin accessibility, a major mode of epigenetic regulation of gene expression. Here we compared chromatin accessibility landscapes of adult mouse dentate granule neurons in vivo before and after synchronous neuronal activation using an assay for transposase-accessible chromatin using sequencing (ATAC-seq). We found genome-wide changes 1 h after activation, with enrichment of gained-open sites at active enhancer regions and at binding sites for AP1-complex components, including c-Fos. Some changes remained stable for at least 24 h. Functional analysis further implicates a critical role of c-Fos in initiating, but not maintaining, neuronal activity-induced chromatin opening. Our results reveal dynamic changes of chromatin accessibility in adult mammalian brains and suggest an epigenetic mechanism by which transient neuronal activation leads to dynamic changes in gene expression via modifying chromatin accessibility.

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Acknowledgements

We thank the members of the Song and Ming laboratories for discussions, K. Christian for comments and Y. Cai and L. Liu for technical support. This work was supported by NIH (R37NS047344 and P01NS097206 to H.S., R35NS097370 and R01MH105128 to G.-l.M.), SFARI (Award 240011 to H.S.), The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to G.-l.M.) and The Brain and Behavior Research Foundation (to Y.S.).

Author information

Affiliations

  1. Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Yijing Su
    • , Jaehoon Shin
    • , Chun Zhong
    • , Sabrina Wang
    • , Prith Roychowdhury
    • , Jongseuk Lim
    • , David Kim
    • , Guo-li Ming
    •  & Hongjun Song
  2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Yijing Su
    • , Jaehoon Shin
    • , Chun Zhong
    • , Guo-li Ming
    •  & Hongjun Song
  3. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Guo-li Ming
    •  & Hongjun Song
  4. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Guo-li Ming

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Contributions

Y.S. and H.S. designed the project. C.Z. prepared the AAV and performed viral injections; Y.S., J.S., S.W., P.R., J.L. and D.K. contributed to data collection, analyses and interpretation. Y.S., J.S., G.-l.M. and H.S. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Hongjun Song.

Integrated supplementary information

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–10 and Supplementary Table 2

  2. 2.

    Supplementary Methods Checklist

Excel files

  1. 1.

    Supplementary Table 1

    Summary of open chromatin regions at E0, E1, E4 and E24.

  2. 2.

    Supplementary Table 3

    Summary of dentate granule neuron-specific open chromatin regions and their associated genes compared to other neuronal subtype cells.

  3. 3.

    Supplementary Table 4

    Summary of differential chromatin opening regions after synchronous neuronal activation from ATAC-seq analysis

  4. 4.

    Supplementary Table 5

    Summary of RNA-seq analyses.

  5. 5.

    Supplementary Table 6

    List of gained-open peaks with cFos binding site at E1 compared to E0.

  6. 6.

    Supplementary Table 7

    Summary of differential peaks under cFos knockdown and overexpression conditions from ATAC-seq analysis.

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DOI

https://doi.org/10.1038/nn.4494

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