肌成纤维细胞
DNA甲基化
肺纤维化
癌症研究
基因沉默
成纤维细胞
纤维化
心脏纤维化
CpG站点
特发性肺纤维化
转化生长因子
生物
博莱霉素
细胞生物学
医学
肺
基因表达
病理
基因
遗传学
内科学
细胞培养
化疗
作者
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
出处
期刊:The European respiratory journal
[European Respiratory Society]
日期:2022-01-27
卷期号:60 (3): 2003697-2003697
被引量:27
标识
DOI:10.1183/13993003.03697-2020
摘要
Although DNA methylation has been recognised in the pathogenesis of idiopathic pulmonary fibrosis (IPF), the exact mechanisms are yet to be fully addressed. Herein, we demonstrate that lungs originated from IPF patients and mice after bleomycin (BLM)-induced pulmonary fibrosis are characterised by altered DNA methylation along with overexpression in myofibroblasts of methyl-CpG-binding domain 2 (MBD2), 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, transforming growth factor (TGF)-β1 induced a positive feedback regulatory loop between TGF-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 enhanced TGF-β/Smad signalling to promote differentiation of fibroblast 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.
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