Journal
NATURE MICROBIOLOGY
Volume 2, Issue 8, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nmicrobiol.2017.86
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Funding
- National Institutes of Health (NIH) [NIAID AI062885, UL1TR001439, NIEHS ES006676]
- National Science Foundation (NSF) [DMS-1361411/DMS-1361318]
- Sealy Center for Molecular Medicine pilot funds
- UTMB Optical Imaging Lab
- Division Of Mathematical Sciences
- Direct For Mathematical & Physical Scien [1361411] Funding Source: National Science Foundation
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Chronic oxidative injury produced by airway disease triggers a transforming growth factor-beta (TGF-beta)-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.
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