Abstract
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.
Footnotes
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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.
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- Received October 1, 2020.
- Accepted December 9, 2021.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org