RT Journal Article
SR Electronic
T1 The methyl-CpG-binding domain 2 facilitates pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 2003697
DO 10.1183/13993003.03697-2020
A1 Yi Wang
A1 Lei Zhang
A1 Teng Huang
A1 Guo-Rao Wu
A1 Qing Zhou
A1 Fa-Xi Wang
A1 Long-Min Chen
A1 Fei Sun
A1 Yongman Lv
A1 Fei Xiong
A1 Shu Zhang
A1 Qilin Yu
A1 Ping Yang
A1 Weikuan Gu
A1 Yongjian Xu
A1 Jianping Zhao
A1 Huilan Zhang
A1 Weining Xiong
A1 Cong-Yi Wang
YR 2021
UL http://erj.ersjournals.com/content/early/2021/12/16/13993003.03697-2020.abstract
AB Although DNA methylation has been recognized in the pathogenesis of idiopathic pulmonary fibrosis (IPF), the exact mechanisms, however, are yet to be fully addressed. Herein, we demonstrated that lungs originated from IPF patients and mice after bleomycin (BLM)-induced pulmonary fibrosis are characterized by the altered DNA methylation along with overexpression of methyl-CpG-binding domain 2 (MBD2) in myofibroblasts, a reader responsible for interpreting DNA methylome-encoded information. Specifically, depletion of Mbd2 in fibroblasts or myofibroblasts protected mice from BLM-induced pulmonary fibrosis coupled with a significant reduction of fibroblast differentiation. Mechanistically, TGF-β1 induced a positive feedback regulatory loop between transforming growth factor-β receptor I (TβRI), Smad3 and Mbd2, and erythroid differentiation regulator 1 (Erdr1). TGF-β1 induced fibroblasts to undergo a global DNA hypermethylation along with Mbd2 overexpression in a TβRI/Smad3 dependent manner, and Mbd2 selectively bound to the methylated CpG DNA within the Erdr1 promoter to repress its expression, through which it enhances TGF-β/Smads signaling to promote fibroblast differentiating into myofibroblast and exacerbate pulmonary fibrosis. Therefore, enhancing Erdr1 expression strikingly reversed established pulmonary fibrosis. Collectively, our data support that strategies aimed at silencing Mbd2 or increasing Erdr1 could be viable therapeutic approaches for prevention and treatment of pulmonary fibrosis in clinical settings.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Wang has nothing to disclose.Conflict of interest: Dr. Zhang has nothing to disclose.Conflict of interest: Dr. Huang has nothing to disclose.Conflict of interest: Dr. Wu has nothing to disclose.Conflict of interest: Dr. Zhou has nothing to disclose.Conflict of interest: Dr. Wang has nothing to disclose.Conflict of interest: Dr. Chen has nothing to disclose.Conflict of interest: Dr. Sun has nothing to disclose.Conflict of interest: Dr. Lv has nothing to disclose.Conflict of interest: Dr. Xiong has nothing to disclose.Conflict of interest: Dr. Zhang has nothing to disclose.Conflict of interest: Dr. Yu has nothing to disclose.Conflict of interest: Dr. Yang has nothing to disclose.Conflict of interest: Dr. Gu has nothing to disclose.Conflict of interest: Dr. Xu has nothing to disclose.Conflict of interest: Dr. Zhao has nothing to disclose.Conflict of interest: Dr. Zhang has nothing to disclose.Conflict of interest: Dr. Xiong has nothing to disclose.Conflict of interest: Dr. Wang has nothing to disclose.