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

Jun Yang, Bing Tian, Hong Sun, Roberto Garofalo, Allan R. Brasier

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number17086
JournalNature Microbiology
Volume2
DOIs
StatePublished - Jun 5 2017

Fingerprint

Interferon Regulatory Factor-1
Epithelial-Mesenchymal Transition
Virus Diseases
Epigenomics
Respiratory Tract Infections
Interferons
Polycomb Repressive Complex 2
Airway Remodeling
Rhinovirus
Respiratory Syncytial Viruses
Transforming Growth Factors
Virus Replication
Antiviral Agents
Zinc Finger E-box-Binding Homeobox 1
Fibrosis
Up-Regulation
Wounds and Injuries

ASJC Scopus subject areas

  • Microbiology
  • Applied Microbiology and Biotechnology
  • Immunology
  • Microbiology (medical)
  • Cell Biology
  • Genetics

Cite this

@article{2aed389ab0ac4cc3a35583a68368003c,
title = "Epigenetic silencing of IRF1 dysregulates type III interferon responses to respiratory virus infection in epithelial to mesenchymal transition",
abstract = "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.",
author = "Jun Yang and Bing Tian and Hong Sun and Roberto Garofalo and Brasier, {Allan R.}",
year = "2017",
month = "6",
day = "5",
doi = "10.1038/nmicrobiol.2017.86",
language = "English (US)",
volume = "2",
journal = "Nature Microbiology",
issn = "2058-5276",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Epigenetic silencing of IRF1 dysregulates type III interferon responses to respiratory virus infection in epithelial to mesenchymal transition

AU - Yang, Jun

AU - Tian, Bing

AU - Sun, Hong

AU - Garofalo, Roberto

AU - Brasier, Allan R.

PY - 2017/6/5

Y1 - 2017/6/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85020467572&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020467572&partnerID=8YFLogxK

U2 - 10.1038/nmicrobiol.2017.86

DO - 10.1038/nmicrobiol.2017.86

M3 - Article

VL - 2

JO - Nature Microbiology

JF - Nature Microbiology

SN - 2058-5276

M1 - 17086

ER -