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RNASeq analysis identifies non-canonical role of STAT2 and IRF9 in the regulation of a STAT1-independent antiviral and immunoregulatory transcriptional program induced by IFNβ and TNFα

Mélissa K. Mariani, View ORCID ProfilePouria Dasmeh, Audray Fortin, Mario Kalamujic, Elise Caron, Alexander N. Harrison, Sandra Cervantes-Ortiz, Espérance Mukawera, View ORCID ProfileAdrian W.R. Serohijos, Nathalie Grandvaux
doi: https://doi.org/10.1101/273623
Mélissa K. Mariani
1CRCHUM - Centre Hospitalier de l’Université de Montréal, Québec, Canada
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Pouria Dasmeh
2Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Qc, Canada
3Centre Robert Cedergren en Bioinformatique et Génomique, Université de Montréal, Qc, Canada
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  • ORCID record for Pouria Dasmeh
Audray Fortin
1CRCHUM - Centre Hospitalier de l’Université de Montréal, Québec, Canada
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Mario Kalamujic
1CRCHUM - Centre Hospitalier de l’Université de Montréal, Québec, Canada
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Elise Caron
1CRCHUM - Centre Hospitalier de l’Université de Montréal, Québec, Canada
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Alexander N. Harrison
1CRCHUM - Centre Hospitalier de l’Université de Montréal, Québec, Canada
4Department of Microbiology and Immunology, McGill University, Qc, Canada
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Sandra Cervantes-Ortiz
1CRCHUM - Centre Hospitalier de l’Université de Montréal, Québec, Canada
5Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Université de Montréal, Qc, Canada
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Espérance Mukawera
1CRCHUM - Centre Hospitalier de l’Université de Montréal, Québec, Canada
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Adrian W.R. Serohijos
2Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Qc, Canada
3Centre Robert Cedergren en Bioinformatique et Génomique, Université de Montréal, Qc, Canada
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  • ORCID record for Adrian W.R. Serohijos
Nathalie Grandvaux
1CRCHUM - Centre Hospitalier de l’Université de Montréal, Québec, Canada
2Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Qc, Canada
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  • For correspondence: nathalie.grandvaux@umontreal.ca
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ABSTRACT

IFNβ plays a critical role in the host defense against pathogens through the induction of hundreds of antiviral and immunoregulatory genes. Response to IFNβ is context-dependent and is prone to crosstalk with other cytokines. Costimulation with IFNβ and TNFα drives a specific delayed transcriptional program composed of genes that are either not responsive to IFNβ or TNFα separately or are only responsive to either one of the cytokine. The signaling mechanisms engaged downstream of the costimulation with IFNβ and TNFα remained elusive. In the present study, we took advantage of STAT1-deficient cells coupled to RNASeq analysis to characterize the genome wide transcriptional profile induced in response to IFNβ and TNFα. We found that costimulation with IFNβ and TNFα induces a broad antiviral and immunoregulatory transcriptional program independently of STAT1. Additional sequencing performed following silencing of STAT2 or IRF9 allowed us to unveil specific independent roles of STAT2 and IRF9 in the regulation of distinct sets of IFNβ and TNFα-induced genes. Consistent with the growing literature, IFNβ and TNFα synergistic action is in part mediated by the concerted action of STAT2 and IRF9, most likely present in a non-canonical complex. Finally, our study reveals previously unrecognized independent roles of STAT2 and IRF9 in the regulation of distinct sets of IFNβ and TNFα-induced genes. Altogether these observations highlight novel STAT1-independent pathways involved in the establishment of a delayed antiviral and immunoregulatory transcriptional program in conditions where elevated levels of both IFNβ and TNFα are present.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 28, 2018.
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RNASeq analysis identifies non-canonical role of STAT2 and IRF9 in the regulation of a STAT1-independent antiviral and immunoregulatory transcriptional program induced by IFNβ and TNFα
Mélissa K. Mariani, Pouria Dasmeh, Audray Fortin, Mario Kalamujic, Elise Caron, Alexander N. Harrison, Sandra Cervantes-Ortiz, Espérance Mukawera, Adrian W.R. Serohijos, Nathalie Grandvaux
bioRxiv 273623; doi: https://doi.org/10.1101/273623
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RNASeq analysis identifies non-canonical role of STAT2 and IRF9 in the regulation of a STAT1-independent antiviral and immunoregulatory transcriptional program induced by IFNβ and TNFα
Mélissa K. Mariani, Pouria Dasmeh, Audray Fortin, Mario Kalamujic, Elise Caron, Alexander N. Harrison, Sandra Cervantes-Ortiz, Espérance Mukawera, Adrian W.R. Serohijos, Nathalie Grandvaux
bioRxiv 273623; doi: https://doi.org/10.1101/273623

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