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IFN-γ influences epithelial anti-viral responses via histone methylation of the RIG-I promoter

IFN-γ influences epithelial anti-viral responses via histone methylation of the RIG-I promoter
IFN-γ influences epithelial anti-viral responses via histone methylation of the RIG-I promoter
The asthmatic lung is prone to respiratory viral infections that exacerbate the symptoms of the underlying disease. Recent work has suggested that a deficient Th1 response in early life may lead to these aberrant anti-viral responses. We investigated whether the inflammatory environment of the airway epithelium could modulate anti-viral gene expression via epigenetic mechanisms, in order to study the development of a long-term dysregulation of innate responses, which are a hallmark of asthma.

We primed AALEB, a human bronchial epithelial cell line, with IFNγ and IL13 and subsequently infected cells with Respiratory Syncytial Virus (RSV) and innate anti-viral genes expression and their epigenetic markers were analysed.

Priming epithelial cells with IFNγ reduced RSV viral load. Microarray analysis identified that IFNγ-priming enhanced 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 Histone3 Lysine9 (H3K9me3) 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 IFNγ may leave an epigenetic mark upon the chromatin that enhances airway cells’ ability to better resist infection possibly via epigenetic upregulation of RIG-I. These observations provide further evidence for a crucial role of IFNγ in the development of mature anti-viral responses within a model of respiratory infection. Further clinical validation is required to determine if this effect in early life leads to changes in anti-viral responses associated with asthma.
IFNγ, cytokine priming, RIG-I, epigenetic regulation of innate immune response, asthma.
1044-1549
428–438
Spalluto, C. Mirella
6802ad50-bc38-404f-9a19-40916425183b
Singhania, Akul
322f628d-5374-49ec-b7d7-13bb3885d636
Cellura, Doriana
e4cffc4c-0e12-40e7-ad13-e90e3fb55332
Woelk, Christopher H.
4d3af0fd-658f-4626-b3b5-49a6192bcf7d
Sanchez-Elsner, Tilman
b8799f8d-e2b4-4b37-b77c-f2f0e8e2070d
Staples, Karl J.
e0e9d80f-0aed-435f-bd75-0c8818491fee
Wilkinson, Thomas M.A.
8c55ebbb-e547-445c-95a1-c8bed02dd652
Spalluto, C. Mirella
6802ad50-bc38-404f-9a19-40916425183b
Singhania, Akul
322f628d-5374-49ec-b7d7-13bb3885d636
Cellura, Doriana
e4cffc4c-0e12-40e7-ad13-e90e3fb55332
Woelk, Christopher H.
4d3af0fd-658f-4626-b3b5-49a6192bcf7d
Sanchez-Elsner, Tilman
b8799f8d-e2b4-4b37-b77c-f2f0e8e2070d
Staples, Karl J.
e0e9d80f-0aed-435f-bd75-0c8818491fee
Wilkinson, Thomas M.A.
8c55ebbb-e547-445c-95a1-c8bed02dd652

Spalluto, C. Mirella, Singhania, Akul, Cellura, Doriana, Woelk, Christopher H., Sanchez-Elsner, Tilman, Staples, Karl J. and Wilkinson, Thomas M.A. (2017) IFN-γ influences epithelial anti-viral responses via histone methylation of the RIG-I promoter. American Journal of Respiratory Cell and Molecular Biology, 57 (4), 428–438. (doi:10.1165/rcmb.2016-0392OC).

Record type: Article

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 Th1 response in early life may lead to these aberrant anti-viral responses. We investigated whether the inflammatory environment of the airway epithelium could modulate anti-viral gene expression via epigenetic mechanisms, in order to study the development of a long-term dysregulation of innate responses, which are a hallmark of asthma.

We primed AALEB, a human bronchial epithelial cell line, with IFNγ and IL13 and subsequently infected cells with Respiratory Syncytial Virus (RSV) and innate anti-viral genes expression and their epigenetic markers were analysed.

Priming epithelial cells with IFNγ reduced RSV viral load. Microarray analysis identified that IFNγ-priming enhanced 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 Histone3 Lysine9 (H3K9me3) 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 IFNγ may leave an epigenetic mark upon the chromatin that enhances airway cells’ ability to better resist infection possibly via epigenetic upregulation of RIG-I. These observations provide further evidence for a crucial role of IFNγ in the development of mature anti-viral responses within a model of respiratory infection. Further clinical validation is required to determine if this effect in early life leads to changes in anti-viral responses associated with asthma.

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Spalluto et al 2017 AJRCMB Accepted Article in Press - Accepted Manuscript
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Accepted/In Press date: 25 April 2017
e-pub ahead of print date: 8 May 2017
Published date: 1 October 2017
Keywords: IFNγ, cytokine priming, RIG-I, epigenetic regulation of innate immune response, asthma.
Organisations: NIHR Southampton Respiratory Biomedical Research Unit, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 408176
URI: https://eprints.soton.ac.uk/id/eprint/408176
ISSN: 1044-1549
PURE UUID: 74cb5610-769b-4b7e-8a72-7f8eebb54d49
ORCID for Karl J. Staples: ORCID iD orcid.org/0000-0003-3844-6457

Catalogue record

Date deposited: 16 May 2017 04:02
Last modified: 03 Dec 2019 06:06

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