m6A modification regulates lung fibroblast-to-myofibroblast transition through modulating KCNH6 mRNA translation

Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal lung disease characterized by progressive and non-reversible abnormal matrix deposition in lung parenchyma. Myofibroblasts originating mainly from resident fibroblasts via fibroblast-to-myofibroblast transition (FMT) are the dominant collagen-p...

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Published in:Molecular therapy 2021-12, Vol.29 (12), p.3436-3448
Main Authors: Zhang, Jia-xiang, Huang, Pei-jie, Wang, Da-peng, Yang, Wen-yu, Lu, Jian, Zhu, Yong, Meng, Xiao-xiao, Wu, Xin, Lin, Qiu-hai, Lv, Hui, Xie, Hui, Wang, Rui-lan
Format: Article
Language:English
Subjects:
fibroblast-to-myofibroblast transition
KCNH6
m6A modification
METTL3
Original
pulmonary fibrosis
YTHDF1
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Summary:Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal lung disease characterized by progressive and non-reversible abnormal matrix deposition in lung parenchyma. Myofibroblasts originating mainly from resident fibroblasts via fibroblast-to-myofibroblast transition (FMT) are the dominant collagen-producing cells in pulmonary fibrosis. N6-methyladenosine (m6A) modification has been implicated in various biological processes. However, the role of m6A modification in pulmonary fibrosis remains elusive. In this study, we reveal that m6A modification is upregulated in a bleomycin (BLM)-induced pulmonary fibrosis mouse model, FMT-derived myofibroblasts, and IPF patient lung samples. Lowering m6A levels through silencing methyltransferase-like 3 (METTL3) inhibits the FMT process in vitro and in vivo. Mechanistically, KCNH6 is involved in the m6A-regulated FMT process. m6A modification regulates the expression of KCNH6 by modulating its translation in a YTH-domain family 1 (YTHDF1)-dependent manner. Together, our study highlights the critical role of m6A modification in pulmonary fibrosis. Manipulation of m6A modification through targeting METTL3 may become a promising strategy for the treatment of pulmonary fibrosis. [Display omitted] m6A modification has been implicated in various biological processes. In this study, Zhang et al. highlight the critical role of m6A modification in pulmonary fibrosis. This study provides novel insights into the mechanism of the fibrotic process and suggests m6A modification intervention may be a promising therapeutic strategy for pulmonary fibrosis.
ISSN:1525-0016
1525-0024
DOI:10.1016/j.ymthe.2021.06.008