Dissecting the function of NSD1 in intestinal epithelium and inflammation

NSD1 (nuclear receptor-binding SET domain protein1, KMT3B) is a histone H3 lysine 36 methyltransferase, which is critical to normal growth and development, and its loss-of-function mutation causes Sotos syndrome, a genetic disorder characterized by overgrowth in childhood, a distinctive facial appearance and developmental delay. Given the prior reports showing that NSD1 decreases H3K27ac at active enhancers and that the H3K27 is associated with intestinal inflammation, we here show that NSD1 maintains intestinal epithelial integrity and inhibits intestinal inflammation in a mouse model that mimics the symptoms and pathology of ulcerative colitis (UC) in humans. Specifically, intestinal epithelial cell (IEC)-specific Nsd1 KO mouse exhibits a significant decrease in antimicrobial peptides (AMPs) genes, which are essential to maintain intestinal homeostasis and mediate epithelial host defense against infection. Collectively, this work uncovered the function of NSD1 in intestinal epithelium sustaining intestinal integrity and protecting that from damage-induced inflammation, which may contribute to prevent the development of GI (gastrointestinal) malignancy caused by chronic intestinal inflammation.