Epigenetic silencing of IRF1 dysregulates type III interferon responses to respiratory virus infection in epithelial to mesenchymal transition.
Nat Microbiol
; 2: 17086, 2017 Jun 05.
Article
em En
| MEDLINE
| ID: mdl-28581456
ABSTRACT
Chronic oxidative injury produced by airway disease triggers a transforming growth factor-ß (TGF-ß)-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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Vírus Sinciciais Respiratórios
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Interferons
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Inativação Gênica
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Fator Regulador 1 de Interferon
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Interações Hospedeiro-Patógeno
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Transição Epitelial-Mesenquimal
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Homeobox 1 de Ligação a E-box em Dedo de Zinco
Limite:
Humans
Idioma:
En
Revista:
Nat Microbiol
Ano de publicação:
2017
Tipo de documento:
Article