Nuclear m6A reader YTHDC1 promotes muscle stem cell activation/proliferation by regulating mRNA splicing and nuclear export
- Chinese University of Hong Kong, China
- 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.
Article and author information
Author details
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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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
