Epithelial NSD2 maintains FMOs-mediated taurine biosynthesis to prevent intestinal barrier disruption

Abstract

Inflammatory bowel disease (IBD) poses a significant challenge due to its intricate pathogenesis. NSD2, a histone methyltransferase responsible for dimethylating histone 3 at lysine 36, is associated with transcriptional activation. However, the precise role of NSD2 in IBD remains unexplored. In this study, we discovered a downregulation of NSD2 in both the intestinal epithelial cells (IECs) of patients and the IBD mouse model. Deficiency of NSD2 in mouse IECs aggravated epithelial barrier disruption and inflammatory response in IBD. Mechanically, NSD2 loss downregulated H3K36me2 and FMO (taurine-synthesis enzyme) mRNA in IECs, resulting in decreased taurine biosynthesis in IECs. Importantly, supplementation with taurine significantly attenuated the symptoms of NSD2 deficiency-induced IBD. These data demonstrate that NSD2 plays a pivotal role in maintaining FMOs-mediated taurine biosynthesis to prevent intestinal inflammation. Our findings also underscore the importance of NSD2-H3K36me2-mediated taurine biosynthesis in maintaining intestinal mucosal barrier homeostasis.