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IFN-γ Influences Epithelial Antiviral Responses via Histone Methylation of the RIG-I Promoter.

Abstract：

:The asthmatic lung is prone to respiratory viral infections that exacerbate the symptoms of the underlying disease. Recent work has suggested that a deficient T-helper cell type 1 response in early life may lead to these aberrant antiviral responses. To study the development of long-term dysregulation of innate responses, which is a hallmark of asthma, we investigated whether the inflammatory environment of the airway epithelium can modulate antiviral gene expression via epigenetic mechanisms. We primed AALEB cells, a human bronchial epithelial cell line, with IFN-γ and IL-13, and subsequently infected the cells with respiratory syncytial virus (RSV). We then analyzed the expression of innate antiviral genes and their epigenetic markers. Priming epithelial cells with IFN-γ reduced the RSV viral load. Microarray analysis identified that IFN-γ priming enhanced retinoic acid-inducible gene (RIG)-I mRNA expression, and this expression correlated with epigenetic changes at the RIG-I promoter that influenced its transcription. Using chromatin immunoprecipitation, we observed a reduction of trimethylated histone 3 lysine 9 at the RIG-I promoter. Addition of inhibitor BIX-01294 to this model indicated an involvement of lysine methyltransferase G9a in RIG-I epigenetic regulation. These data suggest that prior exposure to IFN-γ may leave an epigenetic mark on the chromatin that enhances airway cells' ability to resist infection, possibly via epigenetic upregulation of RIG-I. These observations provide further evidence for a crucial role of IFN-γ in the development of mature antiviral responses within a model of respiratory infection. Further clinical validation is required to determine whether this effect in early life leads to changes in antiviral responses associated with asthma.

journal_name

Am J Respir Cell Mol Biol

journal_title

American journal of respiratory cell and molecular biology

authors

Spalluto CM,Singhania A,Cellura D,Woelk CH,Sanchez-Elsner T,Staples KJ,Wilkinson TMA

doi

10.1165/rcmb.2016-0392OC

subject

Has Abstract

pub_date

2017-10-01 00:00:00

pages

428-438

issue

eissn

1044-1549

issn

1535-4989

journal_volume

pub_type

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IFN-γ Influences Epithelial Antiviral Responses via Histone Methylation of the RIG-I Promoter.