Open AccessThe methyl-CpG-binding domain 2 facilitates pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation
Author(s) -
Yi Wang,
Lei Zhang,
Teng Huang,
Guorao Wu,
Qing Zhou,
Fa-Xi Wang,
Longmin Chen,
Fei Sun,
Yongman Lv,
Fei Xiong,
Shu Zhang,
Qilin Yu,
Ping Yang,
Weikuan Gu,
Yongjian Xu,
Jianping Zhao,
Huilan Zhang,
Weining Xiong,
Cong-Yi Wang
Publication year - 2022
Publication title -
european respiratory journal/the european respiratory journal
Language(s) - English
Resource type - Journals
eISSN - 1399-3003
pISSN - 0903-1936
DOI - 10.1183/13993003.03697-2020
Subject(s) - myofibroblast , dna methylation , pulmonary fibrosis , cardiac fibrosis , cancer research , fibrosis , idiopathic pulmonary fibrosis , gene silencing , fibroblast , transforming growth factor , biology , cpg site , bleomycin , microbiology and biotechnology , medicine , lung , gene expression , pathology , gene , genetics , cell culture , chemotherapy
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.