Nuclear m6A reader YTHDC1 promotes muscle stem cell activation/proliferation by regulating mRNA splicing and nuclear export

  1. Yulong Qiao
  2. Qiang Sun
  3. Xiaona Chen
  4. Liangqiang He
  5. Di Wang
  6. Ruibao Su
  7. Yuanchao Xue
  8. Hao Sun  Is a corresponding author
  9. Huating Wang  Is a corresponding author
  1. Chinese University of Hong Kong, China
  2. Chinese Academy of Sciences, China

Abstract

Skeletal muscle stem cells (also known as satellite cells, SCs) are essential for muscle regeneration and the regenerative activities of SCs are intrinsically governed by gene regulatory mechanisms but the post-transcriptional regulation in SCs remains largely unknown. N(6)-methyladenosine (m6A) modification of RNAs is the most pervasive and highly conserved RNA modification in eukaryotic cells and exerts powerful impact on almost all aspects of mRNA processing which is mainly endowed by its binding with m6A reader proteins. Here in this study, we investigate the previously uncharacterized regulatory roles of YTHDC1, a m6A reader in mouse SCs. Our results demonstrate YTHDC1 is an essential regulator of SC activation and proliferation upon acute injury induced muscle regeneration. The induction of YTHDC1 is indispensable for SC activation and proliferation thus inducible YTHDC1 depletion almost abolishes SC regenerative capacity. Mechanistically, transcriptome-wide profiling using LACE-seq in both SCs and mouse C2C12 myoblasts identifies m6A mediated binding targets of YTHDC1. Next, splicing analysis defines splicing mRNA targets of m6A-YTHDC1. Furthermore, nuclear export analysis also leads to identification of potential mRNA export targets of m6A-YTHDC1 in SCs and C2C12 myoblasts and interestingly some mRNAs can be regulated at both splicing and export levels. Lastly, we map YTHDC1 interacting protein partners in myoblasts and unveil a myriad of factors governing mRNA splicing, nuclear export and transcription, among which hnRNPG appears to be a bona fide interacting partner of YTHDC1. Altogether, our findings uncover YTHDC1 as an essential factor controlling SC regenerative ability through multi-faceted gene regulatory mechanisms in mouse myoblast cells.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE210127.

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

Article and author information

Author details

  1. Yulong Qiao

    Department of Chemical Pathology, Chinese University of Hong Kong, Hong Kong, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Qiang Sun

    Department of Orthopaedics and Traumatology, Chinese University of Hong Kong, Hong Kong, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Xiaona Chen

    Department of Orthopaedics and Traumatology, Chinese University of Hong Kong, Hong Kong, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Liangqiang He

    Department of Chemical Pathology, Chinese University of Hong Kong, Hong Kong, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Di Wang

    Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Ruibao Su

    Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Yuanchao Xue

    Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Hao Sun

    Department of Chemical Pathology, Chinese University of Hong Kong, Hong Kong, China
    For correspondence
    haosun@cuhk.edu.hk
    Competing interests
    The authors declare that no competing interests exist.
  9. Huating Wang

    Department of Chemical Pathology, Chinese University of Hong Kong, Hong Kong, China
    For correspondence
    huating.wang@cuhk.edu.hk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5474-2905

Funding

National Natural Science Foundation of China (82172436)

  • Huating Wang

General Research Funds of Hong Kong (14115319,14100620,14106521)

  • Huating Wang

General Research Funds of Hong Kong (14103522,14120420,14120619)

  • Hao Sun

Collaborative Research Fund from RGC of Hong Kong (C6018-19GF)

  • Huating Wang

Theme-based Research Scheme from RGC of Hong Kong (T13-602/21-N)

  • Huating Wang

Area of Excellence Scheme from RGC of Hong Kong (AoE/M-402/20)

  • Huating Wang

Health@InnoHK program launched by Innovation Technology Commission, the Government of the Hong Kong SAR, China (Center for Neuromusculoskeletal Restorative Medicine (CNRM))

  • Huating Wang

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 handling procedures and protocols were approved by the Animal Experimentation Ethics Committee (AEEC) of CUHK (Ref. No. 19-251-MIS). All animal experiments with iKO mice followed the regulations and guidance of laboratory animals set in CUHK.

Copyright

© 2023, Qiao 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. Yulong Qiao
  2. Qiang Sun
  3. Xiaona Chen
  4. Liangqiang He
  5. Di Wang
  6. Ruibao Su
  7. Yuanchao Xue
  8. Hao Sun
  9. Huating Wang
(2023)
Nuclear m6A reader YTHDC1 promotes muscle stem cell activation/proliferation by regulating mRNA splicing and nuclear export
eLife 12:e82703.
https://doi.org/10.7554/eLife.82703

Share this article

https://doi.org/10.7554/eLife.82703

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