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ISGF3-­Mediated Chromatin Dynamics and Regulation of Type I Interferon-­Stimulated Genes

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Type I interferon (IFN) is the primary antiviral cytokine establishing a broad and potent antiviral response to protect mammalian cells from virus infection. The functional repertoire of IFN extends to innate and adaptive immunity, neoplastic transformation, resistance and cancer immunotherapy. IFN functions are primarily mediated through the Janus kinase (JAK) and signal transducers and activators of transcription (STAT) signaling pathway. Stimulation of the IFN-JAK-STAT signaling cascade drives the expression of hundreds of diverse IFN-stimulated gene (ISG) effectors underlying IFN functions. Similar to other mammalian genes, ISGs are encoded within a chromatin structure in the human genome. ISG expression is activated primarily by the trimeric transcription factor complex, ISG factor 3 (ISGF3), consisting of STAT1, STAT2, and IRF9 proteins. ISGF3 engages target gene promoters and recruits coactivators, Mediator, and RNA polymerase II machinery. To access the native gene template and induce transcription, ISGF3 must engage with chromatinized ISG promoters. ISGF3-associated coactivators with chromatin modifying functions support the notion of a dynamic chromatin regulation in ISG activation; thus, necessitating recruitment of specialized factors to modulate gene accessibility during the IFN response. However, our characterization of the dynamic ISG chromatin environment is insufficient to understand the interplay between ISGF3 and ISG chromatin. In particular, the chromatin architecture at ISG promoters and dynamic alterations following IFN stimulation remain relatively unexplored. To advance our understanding of the dynamic ISG chromatin architecture in relation to ISGF3, I generated genome-wide maps of ISGF3 occupancy to accompany high-resolution nucleosome maps for 20 representative ISGs during steady state and following IFN stimulation. Characterization of the relationship between ISGF3 and ISG promoter nucleosomes led to uncovering a previously unknown role for the histone variant, H2A.Z, in ISG transcription. H2A.Z is present at ISG promoters, but rapidly removed following IFN. H2A.Z eviction from ISG promoter nucleosomes was inversely correlated with ISGF3 recruitment and was found to require the activity of the histone acetyltransferase, GCN5, and the bromodomain protein, BRD2. Reduction of H2A.Z led to enhanced ISGF3 recruitment, increased ISG expression and potentiated antiviral protection, implicating a suppressive role for H2A.Z nucleosomes in the IFN response. Proper gene accessibility is essential to the homeostasis of the IFN response in establishing a protective environment during infection, while preventing adverse effects of a prolonged IFN response. Coordinately controlled H2A.Z removal and incorporation at ISG promoter nucleosomes is an essential component for the activation and repression of ISG effectors for cellular protection and homeostatic integrity.

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