Ileal Crohn's disease exhibits reduced activity of phospholipase C-ß3 (PLC-ß3)-dependent Wnt/b-catenin signaling pathway [ATAC-Seq]

Crohn's disease is a chronic, debilitating inflammatory bowel disease. Here we report a critical role for phospholipase C-ß3 (PLC-ß3) in intestinal homeostasis. In PLC-ß3- deficient mice, exposure to oral dextran sodium sulfate induced lethality and severe inflammation in the small intestine. The lethality was due to PLC-?3 deficiency in multiple non-hematopoietic cell types. PLC-ß3 deficiency resulted in reduced Wnt/?-catenin signaling, which is essential for homeostasis and regeneration of the intestinal epithelium. PLC-ß3 regulated the Wnt/ß-catenin pathway in small intestinal epithelial cells (IECs) at transcriptional, epigenetic, and potentially protein-protein interaction levels. PLC-ß3- deficient IECs were unable to respond to stimulation by R-spondin 1, an enhancer of Wnt/ß-catenin signaling. Reduced expression of PLC-ß3 and its signature genes was found in biopsies of ileal Crohn's disease patients. PLC-ß regulation of Wnt signaling was evolutionally conserved in Drosophila. Our data indicate that reduction of PLC-ß3- mediated Wnt/ß-catenin signaling contributes to the pathogenesis of ileal Crohn's disease. Overall design: To investigate changes of the chromatin accessibility caused by the loss of PLC-b3, we performed ATAC-seq expreiment using PLC-ß3 deficient (KO) or PLC-ß3 sufficient scramble sgRNA treated (Scr) mouse colorectal cancer cell line (CMT-93)