METTL3 modulates colonic epithelium integrity via maintaining the self-renewal and differentiation of Lgr5+ stem cell.

The development and homeostasis of intestinal epithelium are mediated by actively proliferating Lgr5+ stem cells, which possess a remarkable self-renewal and differentiation capacity. Recently, our study demonstrated that N6-methyladenosine (m6A) methylation was essential for the survival of colonic stem cells. Here, we show that methyltransferase-like 3 (METTL3) expression is downregulated in the colon mucosa in ulcerative colitis (UC) patients and strongly associated with the differentiation and maturation of goblet cells during inflammation. In mice, depletion of Mettl3 significantly inhibits the self-renewal and differentiation of Lgr5+ stem cells, especially the differentiation and maturation of goblet cells, resulting in intestinal dysplasia and spontaneous inflammation. Mechanistically, Mettl3 deletion-mediated m6A loss facilitates the expression levels of growth factor receptor binding protein 10 (Grb10) and interferon-related developmental regulator 1 (Ifrd1) via increasing their messenger RNA stability. We further demonstrate that the levels of GRB10 and IFRD1 are negatively correlated with METTL3 level in UC samples. Collectively, our data indicate that METTL3 enhances the self-renewal and differentiation of Lgr5+ stem cells during intestinal development and inflammation, and thus it may be a potential therapeutic target for UC treatment.