Cargando…
Nsun4 and Mettl3 mediated translational reprogramming of Sox9 promotes BMSC chondrogenic differentiation
The chondrogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) has been used in the treatment and repair of cartilage defects; however, the in-depth regulatory mechanisms by which RNA modifications are involved in this process are still poorly understood. Here, we found that...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133052/ https://www.ncbi.nlm.nih.gov/pubmed/35614315 http://dx.doi.org/10.1038/s42003-022-03420-x |
_version_ | 1784713509378981888 |
---|---|
author | Yang, Lin Ren, Zhenxing Yan, Shenyu Zhao, Ling Liu, Jie Zhao, Lijun Li, Zhen Ye, Shanyu Liu, Aijun Li, Xichan Guo, Jiasong Zhao, Wei Kuang, Weihong Liu, Helu Chen, Dongfeng |
author_facet | Yang, Lin Ren, Zhenxing Yan, Shenyu Zhao, Ling Liu, Jie Zhao, Lijun Li, Zhen Ye, Shanyu Liu, Aijun Li, Xichan Guo, Jiasong Zhao, Wei Kuang, Weihong Liu, Helu Chen, Dongfeng |
author_sort | Yang, Lin |
collection | PubMed |
description | The chondrogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) has been used in the treatment and repair of cartilage defects; however, the in-depth regulatory mechanisms by which RNA modifications are involved in this process are still poorly understood. Here, we found that Sox9, a critical transcription factor that mediates chondrogenic differentiation, exhibited enhanced translation by ribosome sequencing in chondrogenic pellets, which was accompanied by increased 5-methylcytosine (m(5)C) and N6-methyladenosine (m(6)A) levels. Nsun4-mediated m(5)C and Mettl3-mediated m(6)A modifications were required for Sox9-regulated chondrogenic differentiation. Interestingly, we showed that in the 3’UTR of Sox9 mRNA, Nsun4 catalyzed the m(5)C modification and Mettl3 catalyzed the m(6)A modification. Furthermore, we found that Nsun4 and Mettl3 co-regulated the translational reprogramming of Sox9 via the formation of a complex. Surface plasmon resonance (SPR) assays showed that this complex was assembled along with the recruitment of Ythdf2 and eEF1α-1. Moreover, BMSCs overexpressing Mettl3 and Nsun4 can promote the repair of cartilage defects in vivo. Taken together, our study demonstrates that m(5)C and m(6)A co-regulate the translation of Sox9 during the chondrogenic differentiation of BMSCs, which provides a therapeutic target for clinical implications. |
format | Online Article Text |
id | pubmed-9133052 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-91330522022-05-27 Nsun4 and Mettl3 mediated translational reprogramming of Sox9 promotes BMSC chondrogenic differentiation Yang, Lin Ren, Zhenxing Yan, Shenyu Zhao, Ling Liu, Jie Zhao, Lijun Li, Zhen Ye, Shanyu Liu, Aijun Li, Xichan Guo, Jiasong Zhao, Wei Kuang, Weihong Liu, Helu Chen, Dongfeng Commun Biol Article The chondrogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) has been used in the treatment and repair of cartilage defects; however, the in-depth regulatory mechanisms by which RNA modifications are involved in this process are still poorly understood. Here, we found that Sox9, a critical transcription factor that mediates chondrogenic differentiation, exhibited enhanced translation by ribosome sequencing in chondrogenic pellets, which was accompanied by increased 5-methylcytosine (m(5)C) and N6-methyladenosine (m(6)A) levels. Nsun4-mediated m(5)C and Mettl3-mediated m(6)A modifications were required for Sox9-regulated chondrogenic differentiation. Interestingly, we showed that in the 3’UTR of Sox9 mRNA, Nsun4 catalyzed the m(5)C modification and Mettl3 catalyzed the m(6)A modification. Furthermore, we found that Nsun4 and Mettl3 co-regulated the translational reprogramming of Sox9 via the formation of a complex. Surface plasmon resonance (SPR) assays showed that this complex was assembled along with the recruitment of Ythdf2 and eEF1α-1. Moreover, BMSCs overexpressing Mettl3 and Nsun4 can promote the repair of cartilage defects in vivo. Taken together, our study demonstrates that m(5)C and m(6)A co-regulate the translation of Sox9 during the chondrogenic differentiation of BMSCs, which provides a therapeutic target for clinical implications. Nature Publishing Group UK 2022-05-25 /pmc/articles/PMC9133052/ /pubmed/35614315 http://dx.doi.org/10.1038/s42003-022-03420-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Yang, Lin Ren, Zhenxing Yan, Shenyu Zhao, Ling Liu, Jie Zhao, Lijun Li, Zhen Ye, Shanyu Liu, Aijun Li, Xichan Guo, Jiasong Zhao, Wei Kuang, Weihong Liu, Helu Chen, Dongfeng Nsun4 and Mettl3 mediated translational reprogramming of Sox9 promotes BMSC chondrogenic differentiation |
title | Nsun4 and Mettl3 mediated translational reprogramming of Sox9 promotes BMSC chondrogenic differentiation |
title_full | Nsun4 and Mettl3 mediated translational reprogramming of Sox9 promotes BMSC chondrogenic differentiation |
title_fullStr | Nsun4 and Mettl3 mediated translational reprogramming of Sox9 promotes BMSC chondrogenic differentiation |
title_full_unstemmed | Nsun4 and Mettl3 mediated translational reprogramming of Sox9 promotes BMSC chondrogenic differentiation |
title_short | Nsun4 and Mettl3 mediated translational reprogramming of Sox9 promotes BMSC chondrogenic differentiation |
title_sort | nsun4 and mettl3 mediated translational reprogramming of sox9 promotes bmsc chondrogenic differentiation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133052/ https://www.ncbi.nlm.nih.gov/pubmed/35614315 http://dx.doi.org/10.1038/s42003-022-03420-x |
work_keys_str_mv | AT yanglin nsun4andmettl3mediatedtranslationalreprogrammingofsox9promotesbmscchondrogenicdifferentiation AT renzhenxing nsun4andmettl3mediatedtranslationalreprogrammingofsox9promotesbmscchondrogenicdifferentiation AT yanshenyu nsun4andmettl3mediatedtranslationalreprogrammingofsox9promotesbmscchondrogenicdifferentiation AT zhaoling nsun4andmettl3mediatedtranslationalreprogrammingofsox9promotesbmscchondrogenicdifferentiation AT liujie nsun4andmettl3mediatedtranslationalreprogrammingofsox9promotesbmscchondrogenicdifferentiation AT zhaolijun nsun4andmettl3mediatedtranslationalreprogrammingofsox9promotesbmscchondrogenicdifferentiation AT lizhen nsun4andmettl3mediatedtranslationalreprogrammingofsox9promotesbmscchondrogenicdifferentiation AT yeshanyu nsun4andmettl3mediatedtranslationalreprogrammingofsox9promotesbmscchondrogenicdifferentiation AT liuaijun nsun4andmettl3mediatedtranslationalreprogrammingofsox9promotesbmscchondrogenicdifferentiation AT lixichan nsun4andmettl3mediatedtranslationalreprogrammingofsox9promotesbmscchondrogenicdifferentiation AT guojiasong nsun4andmettl3mediatedtranslationalreprogrammingofsox9promotesbmscchondrogenicdifferentiation AT zhaowei nsun4andmettl3mediatedtranslationalreprogrammingofsox9promotesbmscchondrogenicdifferentiation AT kuangweihong nsun4andmettl3mediatedtranslationalreprogrammingofsox9promotesbmscchondrogenicdifferentiation AT liuhelu nsun4andmettl3mediatedtranslationalreprogrammingofsox9promotesbmscchondrogenicdifferentiation AT chendongfeng nsun4andmettl3mediatedtranslationalreprogrammingofsox9promotesbmscchondrogenicdifferentiation |