RNASeq analysis identifies non-canonical role of STAT2 and IRF9 in the regulation of a STAT1-independent antiviral and immunoregulatory transcriptional program induced by IFN{beta} and TNF{alpha}

IFN{beta} plays a critical role in the host defense against pathogens through the induction of hundreds of antiviral and immunoregulatory genes. Response to IFN{beta} is context-dependent and is prone to crosstalk with other cytokines. Costimulation with IFN{beta} and TNF drives a specific delayed transcriptional program composed of genes that are either not responsive to IFN{beta} or TNF separately or are only responsive to either one of the cytokine. The signaling mechanisms engaged downstream of the costimulation with IFN{beta} and TNF 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 IFN{beta} and TNF. We found that costimulation with IFN{beta} and TNF 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 IFN{beta} and TNF-induced genes. Consistent with the growing literature, IFN{beta} and TNF 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 IFN{beta} and TNF-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 IFN{beta} and TNF are present.