Nuclear m6A reader YTHDC1 promotes muscle stem cell activation/proliferation by regulating mRNA splicing and nuclear export
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) m...
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| Format: | Article |
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eLife Sciences Publications Ltd
2023-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/82703 |
| _version_ | 1827969190252773376 |
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| author | Yulong Qiao Qiang Sun Xiaona Chen Liangqiang He Di Wang Ruibao Su Yuanchao Xue Hao Sun Huating Wang |
| author_facet | Yulong Qiao Qiang Sun Xiaona Chen Liangqiang He Di Wang Ruibao Su Yuanchao Xue Hao Sun Huating Wang |
| author_sort | Yulong Qiao |
| collection | DOAJ |
| description | 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; it exerts powerful impact on almost all aspects of mRNA processing that is mainly endowed by its binding with m6A reader proteins. In this study, we investigate the previously uncharacterized regulatory roles of YTHDC1, an m6A reader in mouse SCs. Our results demonstrate that 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 the identification of potential mRNA export targets of m6A-YTHDC1 in SCs and C2C12 myoblasts;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 multifaceted gene regulatory mechanisms in mouse myoblast cells. |
| first_indexed | 2024-04-09T18:34:09Z |
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| language | English |
| last_indexed | 2024-04-09T18:34:09Z |
| publishDate | 2023-03-01 |
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| spelling | doaj.art-717eac68fb8543d890f2cee86d0ae3032023-04-11T12:48:30ZengeLife Sciences Publications LtdeLife2050-084X2023-03-011210.7554/eLife.82703Nuclear m6A reader YTHDC1 promotes muscle stem cell activation/proliferation by regulating mRNA splicing and nuclear exportYulong Qiao0https://orcid.org/0000-0002-1952-3077Qiang Sun1Xiaona Chen2Liangqiang He3Di Wang4Ruibao Su5Yuanchao Xue6Hao Sun7Huating Wang8https://orcid.org/0000-0001-5474-2905Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Center for Neuromusculoskeletal Restorative Medicine (CNRM), CUHK InnoHK Centres, The Chinese University of Hong Kong, Hong Kong, ChinaCenter for Neuromusculoskeletal Restorative Medicine (CNRM), CUHK InnoHK Centres, The Chinese University of Hong Kong, Hong Kong, China; Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, ChinaCenter for Neuromusculoskeletal Restorative Medicine (CNRM), CUHK InnoHK Centres, The Chinese University of Hong Kong, Hong Kong, China; Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, ChinaDepartment of Chemical Pathology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Center for Neuromusculoskeletal Restorative Medicine (CNRM), CUHK InnoHK Centres, The Chinese University of Hong Kong, Hong Kong, ChinaKey Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, ChinaDepartment of Chemical Pathology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, ChinaCenter for Neuromusculoskeletal Restorative Medicine (CNRM), CUHK InnoHK Centres, The Chinese University of Hong Kong, Hong Kong, China; Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, ChinaSkeletal 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; it exerts powerful impact on almost all aspects of mRNA processing that is mainly endowed by its binding with m6A reader proteins. In this study, we investigate the previously uncharacterized regulatory roles of YTHDC1, an m6A reader in mouse SCs. Our results demonstrate that 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 the identification of potential mRNA export targets of m6A-YTHDC1 in SCs and C2C12 myoblasts;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 multifaceted gene regulatory mechanisms in mouse myoblast cells.https://elifesciences.org/articles/82703muscle stem cellmuscle regenerationYTHDC1m6AhnRNPG |
| spellingShingle | Yulong Qiao Qiang Sun Xiaona Chen Liangqiang He Di Wang Ruibao Su Yuanchao Xue Hao Sun Huating Wang Nuclear m6A reader YTHDC1 promotes muscle stem cell activation/proliferation by regulating mRNA splicing and nuclear export eLife muscle stem cell muscle regeneration YTHDC1 m6A hnRNPG |
| title | Nuclear m6A reader YTHDC1 promotes muscle stem cell activation/proliferation by regulating mRNA splicing and nuclear export |
| title_full | Nuclear m6A reader YTHDC1 promotes muscle stem cell activation/proliferation by regulating mRNA splicing and nuclear export |
| title_fullStr | Nuclear m6A reader YTHDC1 promotes muscle stem cell activation/proliferation by regulating mRNA splicing and nuclear export |
| title_full_unstemmed | Nuclear m6A reader YTHDC1 promotes muscle stem cell activation/proliferation by regulating mRNA splicing and nuclear export |
| title_short | Nuclear m6A reader YTHDC1 promotes muscle stem cell activation/proliferation by regulating mRNA splicing and nuclear export |
| title_sort | nuclear m6a reader ythdc1 promotes muscle stem cell activation proliferation by regulating mrna splicing and nuclear export |
| topic | muscle stem cell muscle regeneration YTHDC1 m6A hnRNPG |
| url | https://elifesciences.org/articles/82703 |
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