Kaiso overexpression promotes an interferon immune response in murine intestines.

The POZ-ZF transcription factor Kaiso plays important roles in vertebrate development and tumorigenesis and binds DNA with dual-specificity at both a consensus DNA sequence and methyl-CpG sites. In murine intestines, Kaiso overexpression induces a chronic inflammatory phenotype that involves NFκB signaling and neutrophil activation. However, a thorough understanding of the molecular mechanisms and signaling pathways involved in the Kaiso-induced inflammatory response warrant further investigation. In this study, global transcriptomes of ileal tissue from 6-week-old Kaiso overexpressing transgenic (KaisoTg) and non-transgenic (NonTg) control mice were generated by RNA sequencing and compared for differential gene expression prior to histologic inflammation. Functional analysis of differentially expressed genes identified an enrichment of genes involved in type I interferon immune response despite preserved epithelial architecture and the absence of neutrophil infiltration. Irf7, Isg15, Usp18 and Ifi44 were identified as key genes mediating type I interferon signaling in intestinal epithelial cells. We determined that Kaiso binds to and regulates the IRF7 promoter via the consensus Kaiso binding site (KBS). Additionally, promoter-reporter assays confirmed that Kaiso activated the minimal IRF7 promoter-reporter in a KBS-specific and methyl-CpG-independent manner. Collectively, our findings demonstrate that Kaiso overexpression activates a type I interferon gene program that precedes histologic inflammation and implicates IRF7 as a putative Kaiso target gene that mediates this response.