Cargando…

Mettl3-mediated m(6)A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis

N(6)-methyladenosine (m(6)A) is the most abundant epigenetic modification in eukaryotic mRNAs and is essential for multiple RNA processing events during mammalian development and disease control. Here we show that conditional knockout of the m(6)A methyltransferase Mettl3 in bone marrow mesenchymal...

Descripción completa

Detalles Bibliográficos
Autores principales: Wu, Yunshu, Xie, Liang, Wang, Mengyuan, Xiong, Qiuchan, Guo, Yuchen, Liang, Yu, Li, Jing, Sheng, Rui, Deng, Peng, Wang, Yuan, Zheng, Rixin, Jiang, Yizhou, Ye, Ling, Chen, Qianming, Zhou, Xuedong, Lin, Shuibin, Yuan, Quan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235890/
https://www.ncbi.nlm.nih.gov/pubmed/30429466
http://dx.doi.org/10.1038/s41467-018-06898-4
_version_ 1783370930532122624
author Wu, Yunshu
Xie, Liang
Wang, Mengyuan
Xiong, Qiuchan
Guo, Yuchen
Liang, Yu
Li, Jing
Sheng, Rui
Deng, Peng
Wang, Yuan
Zheng, Rixin
Jiang, Yizhou
Ye, Ling
Chen, Qianming
Zhou, Xuedong
Lin, Shuibin
Yuan, Quan
author_facet Wu, Yunshu
Xie, Liang
Wang, Mengyuan
Xiong, Qiuchan
Guo, Yuchen
Liang, Yu
Li, Jing
Sheng, Rui
Deng, Peng
Wang, Yuan
Zheng, Rixin
Jiang, Yizhou
Ye, Ling
Chen, Qianming
Zhou, Xuedong
Lin, Shuibin
Yuan, Quan
author_sort Wu, Yunshu
collection PubMed
description N(6)-methyladenosine (m(6)A) is the most abundant epigenetic modification in eukaryotic mRNAs and is essential for multiple RNA processing events during mammalian development and disease control. Here we show that conditional knockout of the m(6)A methyltransferase Mettl3 in bone marrow mesenchymal stem cells (MSCs) induces pathological features of osteoporosis in mice. Mettl3 loss-of-function results in impaired bone formation, incompetent osteogenic differentiation potential and increased marrow adiposity. Moreover, Mettl3 overexpression in MSCs protects the mice from estrogen deficiency-induced osteoporosis. Mechanistically, we identify PTH (parathyroid hormone)/Pth1r (parathyroid hormone receptor-1) signaling axis as an important downstream pathway for m(6)A regulation in MSCs. Knockout of Mettl3 reduces the translation efficiency of MSCs lineage allocator Pth1r, and disrupts the PTH-induced osteogenic and adipogenic responses in vivo. Our results demonstrate the pathological outcomes of m(6)A mis-regulation in MSCs and unveil novel epitranscriptomic mechanism in skeletal health and diseases.
format Online
Article
Text
id pubmed-6235890
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-62358902018-11-16 Mettl3-mediated m(6)A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis Wu, Yunshu Xie, Liang Wang, Mengyuan Xiong, Qiuchan Guo, Yuchen Liang, Yu Li, Jing Sheng, Rui Deng, Peng Wang, Yuan Zheng, Rixin Jiang, Yizhou Ye, Ling Chen, Qianming Zhou, Xuedong Lin, Shuibin Yuan, Quan Nat Commun Article N(6)-methyladenosine (m(6)A) is the most abundant epigenetic modification in eukaryotic mRNAs and is essential for multiple RNA processing events during mammalian development and disease control. Here we show that conditional knockout of the m(6)A methyltransferase Mettl3 in bone marrow mesenchymal stem cells (MSCs) induces pathological features of osteoporosis in mice. Mettl3 loss-of-function results in impaired bone formation, incompetent osteogenic differentiation potential and increased marrow adiposity. Moreover, Mettl3 overexpression in MSCs protects the mice from estrogen deficiency-induced osteoporosis. Mechanistically, we identify PTH (parathyroid hormone)/Pth1r (parathyroid hormone receptor-1) signaling axis as an important downstream pathway for m(6)A regulation in MSCs. Knockout of Mettl3 reduces the translation efficiency of MSCs lineage allocator Pth1r, and disrupts the PTH-induced osteogenic and adipogenic responses in vivo. Our results demonstrate the pathological outcomes of m(6)A mis-regulation in MSCs and unveil novel epitranscriptomic mechanism in skeletal health and diseases. Nature Publishing Group UK 2018-11-14 /pmc/articles/PMC6235890/ /pubmed/30429466 http://dx.doi.org/10.1038/s41467-018-06898-4 Text en © The Author(s) 2018 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/.
spellingShingle Article
Wu, Yunshu
Xie, Liang
Wang, Mengyuan
Xiong, Qiuchan
Guo, Yuchen
Liang, Yu
Li, Jing
Sheng, Rui
Deng, Peng
Wang, Yuan
Zheng, Rixin
Jiang, Yizhou
Ye, Ling
Chen, Qianming
Zhou, Xuedong
Lin, Shuibin
Yuan, Quan
Mettl3-mediated m(6)A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis
title Mettl3-mediated m(6)A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis
title_full Mettl3-mediated m(6)A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis
title_fullStr Mettl3-mediated m(6)A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis
title_full_unstemmed Mettl3-mediated m(6)A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis
title_short Mettl3-mediated m(6)A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis
title_sort mettl3-mediated m(6)a rna methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235890/
https://www.ncbi.nlm.nih.gov/pubmed/30429466
http://dx.doi.org/10.1038/s41467-018-06898-4
work_keys_str_mv AT wuyunshu mettl3mediatedm6arnamethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosis
AT xieliang mettl3mediatedm6arnamethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosis
AT wangmengyuan mettl3mediatedm6arnamethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosis
AT xiongqiuchan mettl3mediatedm6arnamethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosis
AT guoyuchen mettl3mediatedm6arnamethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosis
AT liangyu mettl3mediatedm6arnamethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosis
AT lijing mettl3mediatedm6arnamethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosis
AT shengrui mettl3mediatedm6arnamethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosis
AT dengpeng mettl3mediatedm6arnamethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosis
AT wangyuan mettl3mediatedm6arnamethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosis
AT zhengrixin mettl3mediatedm6arnamethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosis
AT jiangyizhou mettl3mediatedm6arnamethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosis
AT yeling mettl3mediatedm6arnamethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosis
AT chenqianming mettl3mediatedm6arnamethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosis
AT zhouxuedong mettl3mediatedm6arnamethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosis
AT linshuibin mettl3mediatedm6arnamethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosis
AT yuanquan mettl3mediatedm6arnamethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosis