Deletion of Bmal1 in Intestinal Epithelium Protects against Colonic Inflammation by Suppressing the Apoptosis Pathway (CUT&Tag)
The circadian clock has been shown to regulate inflammatory bowel disease (IBD), but the underlying mechanisms remain unclear. Here, we observed that the mice in the active phase of the circadian clock were more tolerant to dextrose sodium sulfate (DSS)-induced colitis, compared to those in the resting phase. Furthermore, we found that the circadian gene Bmal1 displayed a dynamic expression pattern in mouse colonic epithelium during the circadian clock, with a high level in the resting phase and a low in the active phase. Ablation of Bmal1 in the intestinal epithelium reduced inflammatory symptoms in the colon of the DSS-treated mice. The mice with Bmal1 deletion exhibited no obvious disruption on intestinal homeostasis, rather were more resistant to DSS-induced inflammation, with less body weight change, fewer pathological symptoms, and greater epithelial integrity, compared to the control group. Mechanistically, BMAL1 promoted apoptosis by binding to the apoptosis-related genes, such as Bax, P53 and Bak1, and transcriptionally activating their expression. Collectively, our results reveal the Bmal1-centered circadian clock is involved in intestinal repair upon injure. Clinically, targeting Bmal1 function may be a promising approach to treat inflammation-related gastrointestinal tract diseases. Overall design: To further reveal the underlying mechanism by which Bmal1 governs the progression of colitis, we performed CUT&Tag-seq in mouse colonic organoids.