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

Nature Microbiology volume 2, Article number: 17086 (2017) Cite this article

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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.

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Figure 1: Deficient type I/III IFN responses in TGF-β-induced EMT.
Figure 2: IRF1 silencing dysregulates the IFN response in TGF-β-induced EMT.
Figure 3: CRISPR/Cas9-mediated IRF1 gene knockout.
Figure 4: ZEB1 downregulates the IFN response in hSAECs and TGF-β-induced EMT-hSAECs.
Figure 5: ZEB1 downregulates the IFN response via epigenetic silencing of IRF1.
Figure 6: ZEB1-mediated epigenetic regulation of IRF1.

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Acknowledgements

This work was supported, in part, by National Institutes of Health (NIH) grants NIAID AI062885 (to A.R.B.), UL1TR001439 (to A.R.B.) and NIEHS ES006676 (to J.Y. and A.R.B.), National Science Foundation (NSF) grant DMS-1361411/DMS-1361318 (to A.R.B.) and Sealy Center for Molecular Medicine pilot funds. The authors thank C.M. Rice and J.E. Gern for sharing reagents, acknowledge research support from the UTMB Optical Imaging Lab and thank D. Konkel for critically editing the manuscript.

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Authors and Affiliations

  1. Departments of Internal Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, 77555, Texas, USA

    Jun Yang, Bing Tian, Hong Sun & Allan R. Brasier

  2. Sealy Center for Molecular Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, 77555, Texas, USA

    Jun Yang, Bing Tian, Roberto P. Garofalo & Allan R. Brasier

  3. Department of Pediatrics, University of Texas Medical Branch, 301 University Boulevard, Galveston, 77555, Texas, USA

    Roberto P. Garofalo

  4. Institute for Translational Sciences, University of Texas Medical Branch, 301 University Boulevard, Galveston, 77555, Texas, USA

    Allan R. Brasier

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Contributions

A.R.B. and J.Y. conceived and conducted experiments, analysed results and wrote the paper. H.S. and B.T. performed experiments and collected data. R.P.G. contributed to RSV-related experiments.

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Correspondence to Jun Yang or Allan R. Brasier.

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Yang, J., Tian, B., Sun, H. et al. Epigenetic silencing of IRF1 dysregulates type III interferon responses to respiratory virus infection in epithelial to mesenchymal transition. Nat Microbiol 2, 17086 (2017). https://doi.org/10.1038/nmicrobiol.2017.86

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