Setdb1 in required for intestinal epithelial differentiation and the prevention of intestinal inflammation

The intestinal epithelium is a complex, constitutively renewing tissue composed of functionally distinct intestinal epithelial cells (IECs), whose specific cell fates are established and maintained through cell-specific activity of transcription factors, as well as precise gene silencing by chromatin compaction. By facilitating chromatin condensation through histone modification, SETDB1, a histone-lysine N-methyltransferase, is one of the central factors involved in regulation of epigenetic transcriptional repression. Therefore, we set out to study the potential roles of SETDB1 in intestinal epithelial homeostasis and inflammatory bowel disease (IBD). We used RNA-sequencing to profile gene expression changes in intestinal epithelial cells of mice with tamoxifen (TAM)-inducible (Villin-CreERT2) IEC-specific deletion of Setdb1 on day 2 post TAM-injection start, compared to TAM-treated wild-type littermates. We find an expression profile which indicates intestinal epithelial cell death and induction of type I interferon signaling, as a result of de-repression of endogenous retroviruses. RNA seq analysis of mouse intestinal epithelial crypt cells in mice with intestinal epithelial-specific loss of Setdb1, and wildtype littermates on day 2 post-tamoxifen injection start.