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

Mariani, M.; Dasmeh, P.; Fortin, A.; Kalamujic, M.; Caron, E.; Harrison, A. N.; Cervantes-Ortiz, S.; Mukawera, E.; Serohijos, A.; Grandvaux, N.

doi:10.1101/273623

bioRxiv · 10.1101/273623

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

Mariani, M.·Dasmeh, P.·Fortin, A.·Kalamujic, M.·Caron, E.·Harrison, A. N.·Cervantes-Ortiz, S.·Mukawera, E.·Serohijos, A.·Grandvaux, N.

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Abstract

IFN{beta} typically induces an antiviral and immunoregulatory transcriptional program through the activation of ISGF3 (STAT1, STAT2 and IRF9) transcriptional complexes. The response to IFN{beta} is context-dependent and is prone to crosstalk with other cytokines, such as TNF IFN{beta} and TNF synergize to drive a specific delayed transcriptional program. Previous observation led to the hypothesis that an alternative STAT1-independent pathway involving STAT2 and IRF9 might be involved in gene induction by the combination of IFN{beta} and TNF. Using genome wide transcriptional profiling by RNASeq, we found that the costimulation with IFN{beta} and TNF induces a broad antiviral and immunoregulatory transcriptional program independently of STAT1. Additionally, STAT2 and IRF9 are involved in the regulation of only a subset of these STAT1-independent genes. Consistent with the growing literature, STAT2 and IRF9 act in concert to regulate a subgroup of these genes. Unexpectedly, STAT2 and IRF9 were also engaged in specific independent pathways to regulate distinct sets of IFN{beta} and TNF-induced genes. Altogether these observations highlight the existence of distinct previously unrecognized non-canonical STAT1-independent, but STAT2 and/or IRF9-dependent pathways in the establishment of a delayed antiviral and immunoregulatory transcriptional program in conditions where elevated levels of both IFN{beta} and TNF are present.

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Mariani, M., Dasmeh, P., Fortin, A., Kalamujic, M., Caron, E., Harrison, A. N., Cervantes-Ortiz, S., Mukawera, E., Serohijos, A., Grandvaux, N.. 2018-02-28. 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. https://doi.org/10.1101/273623

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