Actin-related protein 5 functions as a novel modulator of MyoD and MyoG in skeletal muscle and in rhabdomyosarcoma

  1. Tsuyoshi Morita  Is a corresponding author
  2. Ken'ichiro Hayashi
  1. Wakayama Medical University, Japan
  2. Osaka University, Japan

Abstract

Myogenic regulatory factors (MRFs) are pivotal transcription factors in myogenic differentiation. MyoD commits cells to the skeletal muscle lineage by inducing myogenic genes through recruitment of chromatin remodelers to its target loci. This study showed that Actin-related protein 5 (Arp5) acts as an inhibitory regulator of MyoD and MyoG by binding to their cysteine-rich (CR) region, which overlaps with the region essential for their epigenetic functions. Arp5 expression was faint in skeletal muscle tissues. Excessive Arp5 in mouse hind limbs caused skeletal muscle fiber atrophy. Further, Arp5 overexpression in myoblasts inhibited myotube formation by diminishing myogenic gene expression, whereas Arp5 depletion augmented myogenic gene expression. Arp5 disturbed MyoD-mediated chromatin remodeling through competition with the three-amino-acid-loop-extension-class homeodomain transcription factors the Pbx1–Meis1 heterodimer for binding to the CR region. This antimyogenic function was independent of the INO80 chromatin remodeling complex, although Arp5 is an important component of that. In rhabdomyosarcoma (RMS) cells, Arp5 expression was significantly higher than in normal myoblasts and skeletal muscle tissue, probably contributing to MyoD and MyoG activity dysregulation. Arp5 depletion in RMS partially restored myogenic properties while inhibiting tumorigenic properties. Thus, Arp5 is a novel modulator of MRFs in skeletal muscle differentiation.

Data availability

DNA microarray data have been deposited in the GEO database https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE169681 (accession no. GSE169681).ChIP-Seq data have been deposited in the DDBJ database https://ddbj.nig.ac.jp/resource/bioproject/PRJDB13012 (Run accession no. DRR345782-DRR345785).All data generated or analysed during this study are included in the manuscript and supporting files; Source Data files have been provided for Figures 1, 2, 3, 4, 5, 6 and 7.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Tsuyoshi Morita

    Department of Biology, Wakayama Medical University, Wakayama, Japan
    For correspondence
    tsuyo@wakayama-med.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9022-298X
  2. Ken'ichiro Hayashi

    Department of RNA Biology and Neuroscience, Osaka University, Osaka, Japan
    Competing interests
    The authors declare that no competing interests exist.

Funding

Japan Society for the Promotion of Science (KAKENHI 15K07076)

  • Tsuyoshi Morita

Japan Society for the Promotion of Science (KAKENHI 18K06913)

  • Tsuyoshi Morita

Japan Society for the Promotion of Science (KAKENHI 19K07351)

  • Ken'ichiro Hayashi

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

Ethics

Animal experimentation: All animal experiments were conducted in accordance with the guidelines for animal experiments specified by the Wakayama Medical University, Japan, and Osaka University School of Medicine, Japan. The Protocols were approved by the Committee on the Ethics of Animal Experiments of the Wakayama Medical University (Permit Number: 900 ) and Osaka University School of Medicine (Permit Number: 28-018).

Reviewing Editor

  1. Irwin Davidson, Institut de Génétique et de Biologie Moléculaire et Cellulaire, France

Version history

  1. Preprint posted: May 27, 2021 (view preprint)
  2. Received: February 9, 2022
  3. Accepted: March 28, 2022
  4. Accepted Manuscript published: March 29, 2022 (version 1)
  5. Version of Record published: April 5, 2022 (version 2)

Copyright

© 2022, Morita & Hayashi

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. Tsuyoshi Morita
  2. Ken'ichiro Hayashi
(2022)
Actin-related protein 5 functions as a novel modulator of MyoD and MyoG in skeletal muscle and in rhabdomyosarcoma
eLife 11:e77746.
https://doi.org/10.7554/eLife.77746

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https://doi.org/10.7554/eLife.77746

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