The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression program to control neurite outgrowth

Abstract

The mitotic deacetylase complex (MiDAC) is a recently identified histone deacetylase (HDAC) complex. While other HDAC complexes have been implicated in neurogenesis, the physiological role of MiDAC remains unknown. Here, we show that MiDAC constitutes an important regulator of neural differentiation. We demonstrate that MiDAC functions as a modulator of a neurodevelopmental gene expression program and binds to important regulators of neurite outgrowth. MiDAC upregulates gene expression of pro-neural genes such as those encoding the secreted ligands SLIT3 and NETRIN1 (NTN1) by a mechanism suggestive of H4K20ac removal on promoters and enhancers. Conversely, MiDAC inhibits gene expression by reducing H3K27ac on promoter-proximal and -distal elements of negative regulators of neurogenesis. Furthermore, loss of MiDAC results in neurite outgrowth defects that can be rescued by supplementation with SLIT3 and/or NTN1. These findings indicate a crucial role for MiDAC in regulating the ligands of the SLIT3 and NTN1 signaling axes to ensure the proper integrity of neurite development.

Data availability

RNA-sequencing and ChIP-sequencing data have been deposited in GEO under the accession code GSE131062. All data generated or analyzed during this study are included in the manuscript and supporting files.

The following data sets were generated

Article and author information

Author details

  1. Baisakhi Mondal

    Cell & Molecular Biology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Hongjian Jin

    Cell & Molecular Biology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Satish Kallappagoudar

    Pathology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yurii Sedkov

    Cell & Molecular Biology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Tanner Martinez

    Cell & Molecular Biology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Monica F Sentmanat

    Genetics, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Greg J Poet

    Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Chunliang Li

    Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5938-5510
  9. Yiping Fan

    Computational Biology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Shondra M Pruett-Miller

    Department of Cell and Molecular Biology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3793-585X
  11. Hans-Martin Herz

    Cell & Molecular Biology, St Jude Children's Research Hospital, Memphis, United States
    For correspondence
    hans-martin.herz@stjude.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4780-9176

Funding

National Cancer Institute

  • Hans-Martin Herz

American Lebanese Syrian Associated Charities

  • Hans-Martin Herz

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2020, Mondal et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Baisakhi Mondal
  2. Hongjian Jin
  3. Satish Kallappagoudar
  4. Yurii Sedkov
  5. Tanner Martinez
  6. Monica F Sentmanat
  7. Greg J Poet
  8. Chunliang Li
  9. Yiping Fan
  10. Shondra M Pruett-Miller
  11. Hans-Martin Herz
(2020)
The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression program to control neurite outgrowth
eLife 9:e57519.
https://doi.org/10.7554/eLife.57519

Share this article

https://doi.org/10.7554/eLife.57519

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