Consequences of a Stat1 gain-of-function mutation in gene expression and viral response

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Project Summary/Abstract Stat proteins are major drivers of gene expression and genetic variations are linked to many immune pathologies, indicating the importance of Stat proteins in regulating gene expression in health and disease. In addition, Stat proteins themselves must be regulated. Indeed, cytokine signaling can be tuned by the relative abundance and activation of Stat proteins. One disease example of altered tuning of Stat signaling is the heterozygous autosomal dominant gain-of-function (GOF) Stat1 disorder. Stat1-GOF mutations are located in its coil-coil domain or DNA binding domain and result in heightened Stat1 activation/phosphorylation after cytokine stimulation. Consequently, Stat1-activating cytokines induce elevated gene expression in samples from Stat1-GOF patients. This disorder was first described in patients with chronic mucosal candidiasis (CMC) and later attributed to a broad clinical phenotype, including chronic infections associated with primary immunodeficiencies (fungal, bacterial, viral), autoimmunity, and cancer. A simple view of this disorder is that enhanced type 1 immunity/IFN-gamma production inhibits type 3/Th17 responses and may thus explain fungal disease, however many patients also develop chronic viral infections which typically requires type 1 immunity for viral clearance. This paradox emphasizes that there is still a critical need to understand the basic principles of cytokine signaling, specifically how a Stat1-GOF mutation alters the cytokine output. Using a new mouse model with mutated Stat1, we will determine in Aim 1 how a Stat1-GOF mutation alters the transcriptome, chromatin landscape, and Stat1/Stat4 binding in IL-12-stimulated NK cells, and in Aim 2 examine how Stat1- GOF mice respond to MCMV infection. These results will provide critical new insights into basic principles of canonical cell signaling pathway and mechanisms of transcriptional regulation.