Epigenetic silencing of IRF1 dysregulates type III interferon responses to respiratory virus infection in epithelial to mesenchymal transition

• Published in: Nature microbiology Vol. 2; no. 8; p. 17086
• Main Authors: Yang, Jun, Tian, Bing, Sun, Hong, Garofalo, Roberto P., Brasier, Allan R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.06.2017; Nature Publishing Group
• Subjects: 14; 14/63; 38; 38/77; 42; 42/41; 631/250/262; 631/326/596/2555; 631/326/596/2557; 64; 64/60; 692/420/254; Allergic diseases; Antiviral Agents - metabolism; Cells, Cultured; Chronic infection; Epigenesis, Genetic; Epigenetics; Epithelial Cells - physiology; Epithelial Cells - virology; Epithelial-Mesenchymal Transition; Fibrosis; Gene Silencing; Homeobox; Host-Pathogen Interactions; Humans; Immune Evasion; Infectious Diseases; Interferon; Interferon regulatory factor; Interferon regulatory factor 1; Interferon regulatory factor 3; Interferon Regulatory Factor-1 - biosynthesis; Interferons - metabolism; Life Sciences; Medical Microbiology; Mesenchyme; Microbiology; Mucosa; Parasitology; Polycomb group proteins; Respiratory syncytial virus; Respiratory Syncytial Viruses - physiology; Respiratory tract diseases; Rhinovirus; Transforming growth factor-b; Virology; Zinc Finger E-box-Binding Homeobox 1 - metabolism; Zinc finger proteins
• ISSN: 2058-5276; 2058-5276
• DOI: 10.1038/nmicrobiol.2017.86

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.