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.

Metrics

  • 2,601
    views
  • 326
    downloads
  • 25
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
    Hans Tobias Gustafsson, Lucas Ferguson ... Oliver J Rando
    Research Article

    Among the major classes of RNAs in the cell, tRNAs remain the most difficult to characterize via deep sequencing approaches, as tRNA structure and nucleotide modifications can each interfere with cDNA synthesis by commonly-used reverse transcriptases (RTs). Here, we benchmark a recently-developed RNA cloning protocol, termed Ordered Two-Template Relay (OTTR), to characterize intact tRNAs and tRNA fragments in budding yeast and in mouse tissues. We show that OTTR successfully captures both full-length tRNAs and tRNA fragments in budding yeast and in mouse reproductive tissues without any prior enzymatic treatment, and that tRNA cloning efficiency can be further enhanced via AlkB-mediated demethylation of modified nucleotides. As with other recent tRNA cloning protocols, we find that a subset of nucleotide modifications leave misincorporation signatures in OTTR datasets, enabling their detection without any additional protocol steps. Focusing on tRNA cleavage products, we compare OTTR with several standard small RNA-Seq protocols, finding that OTTR provides the most accurate picture of tRNA fragment levels by comparison to "ground truth" Northern blots. Applying this protocol to mature mouse spermatozoa, our data dramatically alter our understanding of the small RNA cargo of mature mammalian sperm, revealing a far more complex population of tRNA fragments - including both 5′ and 3′ tRNA halves derived from the majority of tRNAs – than previously appreciated. Taken together, our data confirm the superior performance of OTTR to commercial protocols in analysis of tRNA fragments, and force a reappraisal of potential epigenetic functions of the sperm small RNA payload.

    1. Chromosomes and Gene Expression
    Ashwin Govindan, Nicholas K Conrad
    Research Article

    O-GlcNAcylation is the reversible post-translational addition of β-N-acetylglucosamine to serine and threonine residues of nuclear and cytoplasmic proteins. It plays an important role in several cellular processes through the modification of thousands of protein substrates. O-GlcNAcylation in humans is mediated by a single essential enzyme, O-GlcNAc transferase (OGT). OGT, together with the sole O-GlcNAcase OGA, form an intricate feedback loop to maintain O-GlcNAc homeostasis in response to changes in cellular O-GlcNAc using a dynamic mechanism involving nuclear retention of its fourth intron. However, the molecular mechanism of this dynamic regulation remains unclear. Using an O-GlcNAc responsive GFP reporter cell line, we identify SFSWAP, a poorly characterized splicing factor, as a trans-acting factor regulating OGT intron detention. We show that SFSWAP is a global regulator of retained intron splicing and exon skipping that primarily acts as a negative regulator of splicing. In contrast, knockdown of SFSWAP leads to reduced inclusion of a ‘decoy exon’ present in the OGT retained intron which may mediate its role in OGT intron detention. Global analysis of decoy exon inclusion in SFSWAP and UPF1 double knockdown cells indicate altered patterns of decoy exon usage. Together, these data indicate a role for SFSWAP as a global negative regulator of pre-mRNA splicing and positive regulator of intron retention.