STAT1 and STAT2 proteins are key mediators of type I and type III interferon (IFN) signaling, and are essential components of the cellular antiviral response and adaptive immunity. They associate with IFN regulatory factor 9 (IRF9) to form a heterotrimeric transcription factor complex known as ISGF3. The regulation of IFN-stimulated gene (ISG) expression has served as a model of JAK-STAT signaling and mammalian transcriptional regulation, but to date has primarily been analyzed at the single gene level. While many aspects of ISGF3-mediated gene regulation are thought to be common features applicable to several ISGs, there are also many reports of distinct cases of non-canonical STAT1 or STAT2 signaling events and distinct patterns of co-regulators that contribute to gene-specific transcription. Recent genome-wide studies have begun to uncover a more complete profile of ISG regulation, moving toward a genome-wide understanding of general mechanisms that underlie gene-specific behaviors.

SummaryType I interferon (IFN)-stimulated gene (ISG) expression requires interaction between a transcription factor complex, ISGF3, and target gene promoters to initiate transcription and protection against infection. To uncover chromatin regulatory features of this antiviral immune response, IFN-induced nucleosome and histone dynamics of human ISG loci were examined. ISGF3 recruitment after IFN stimulation was accompanied by nucleosome reorganization at promoters and gene bodies. IFN stimulation induced loss of core histones H2B, H3, and H4, as well as H2A.Z at ISG promoters. A strong correlation was found between H2A.Z occupancy and ISGF3 target sites, and IFN-stimulated H2A.Z removal requires STAT1, STAT2, and IRF9. Neither INO80 nor SWI/SNF participate in IFN-driven H2A.Z eviction, but GCN5 and BRD2 are required. Interference with H2A.Z expression enhanced ISGF3 recruitment to ISG promoters, ISG mRNA expression, and IFN-stimulated antiviral immunity. This indicates that H2A.Z nucleosomes at ISG promoters restrict optimal ISGF3 engagement and modulate the biological response to IFN.

In response to virus infections, a cell autonomous, transcription-based antiviral program is engaged to create resistance, impair pathogen replication, and alert professional cells in innate and adaptive immunity. This dual phase antiviral program consists of type I interferon (IFN) production followed by the response to IFN signaling. Pathogen recognition leads to activation of IRF and NFκB factors that function independently and together to recruit cellular coactivators that remodel chromatin, modify histones and activate RNA polymerase II (Pol II) at target gene loci, including the well-characterized IFNβ enhanceosome. In the subsequent response to IFN, a receptor-mediated JAK-STAT signaling cascade directs the assembly of the IRF9-STAT1-STAT2 transcription factor complex called ISGF3, which recruits its own cohort of remodelers, coactivators, and Pol II machinery to activate transcription of a wide range of IFN-stimulated genes. Regulation of the IFN and antiviral gene regulatory networks is not only important for driving innate immune responses to infections, but also may inform treatment of a growing list of chronic diseases that are characterized by hyperactive and constitutive IFN and IFN-stimulated gene (ISG) expression. Here, gene-specific and genome-wide investigations of the chromatin landscape at IFN and ISGs is discussed in parallel with IRF- and STAT-dependent regulation of Pol II transcription.