内部收益率1
生物
干扰素调节因子
基因沉默
上皮-间质转换
细胞生物学
干扰素
基因敲除
癌症研究
下调和上调
免疫学
转录因子
先天免疫系统
免疫系统
细胞培养
遗传学
基因
作者
Jun Yang,Bing Tian,Hong Sun,Robert Garofalo,Allan R. Brasier
出处
期刊:Nature microbiology
日期:2017-06-05
卷期号:2 (8)
被引量:49
标识
DOI:10.1038/nmicrobiol.2017.86
摘要
Chronic oxidative injury produced by airway disease triggers a transforming growth factor-β (TGF-β)-mediated epigenetic reprogramming known as the epithelial–mesenchymal transition (EMT). We observe that EMT silences protective mucosal interferon (IFN)-I and III production associated with enhanced rhinovirus (RV) and respiratory syncytial virus (RSV) replication. Mesenchymal transitioned cells are defective in inducible interferon regulatory factor 1 (IRF1) expression by occluding RelA and IRF3 access to the promoter. IRF1 is necessary for the expression of type III IFNs (IFNLs 1 and 2/3). Induced by the EMT, zinc finger E-box binding homeobox 1 (ZEB1) binds and silences IRF1. Ectopic ZEB1 is sufficient for IRF1 silencing, whereas ZEB1 knockdown partially restores IRF1-IFNL upregulation. ZEB1 silences IRF1 through the catalytic activity of the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), forming repressive H3K27(me3) marks. We observe that IRF1 expression is mediated by ZEB1 de-repression, and our study demonstrates how airway remodelling/fibrosis is associated with a defective mucosal antiviral response through ZEB1-initiated epigenetic silencing. This study explores the mechanism for enhanced respiratory virus replication in airway epithelial cells subject to mesenchymal reprogramming, implicating a role for epigenetic silencing interferon pathways.
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