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

Abstract

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.

• Authors: Jia-Xiang Zhang, Pei-Jie Huang, Da-Peng Wang, Wen-Yu Yang, Jian Lu, Yong Zhu, Xiao-Xiao Meng, Xin Wu, Qiu-Hai Lin, Hui Lv, Hui Xie, Rui-Lan Wang
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 29 Issue 12 Pg. 3436-3448 (12 01 2021) ISSN: 1525-0024 [Electronic] United States
• PMID: 34111558 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• Ether-A-Go-Go Potassium Channels
• KCNH6 protein, human
• Bleomycin
• Methyltransferases
• METTL3 protein, human

Topics

• Animals
• Bleomycin (adverse effects)
• Ether-A-Go-Go Potassium Channels (adverse effects, metabolism)
• Fibroblasts (metabolism)
• Humans
• Idiopathic Pulmonary Fibrosis (chemically induced, genetics, therapy)
• Lung (metabolism)
• Methyltransferases (metabolism)
• Mice
• Mice, Inbred C57BL
• Myofibroblasts (metabolism)
• Protein Biosynthesis