m6A mRNA modification maintains colonic epithelial cell homeostasis via NF-κB-mediated anti-apoptotic pathway

Zhang T#, Ding C#*, Chen H# Zhao J, Chen J, Chen B, Mao K, Hao Y, Roulis M, Xu H, Kluger Y, Zou Q, Ye Y, Zhan M*, Flavell RA*, Li HB*. Science Advances. 2022 Mar 25

We propose a role of m6A mRNA modification in maintaining normal colonic epithelial cell homeostasis by regulating the stability of Nfkbia mRNA, one of NF-kB inhibitors. We observed wasting phenotypes and spontaneous colitis in Mettl14fl/fl VillinCre mice, suggesting that m6A modification may be implicated in proper colonic epithelial development. Following experiments found increased the death of colonic epithelial cells in Mettl14fl/fl VillinCre and Lgr5CreERT models. Subsequently, we detected changes within the colonic cellular composition and determined that m6A depletion led to the loss of colonic stem cell population, which disrupted the subsequent function and maturation of the colonic epithelial cells. Further analysis detected differential gene expression, including an upregulation of mRNA and protein level of Nfkbia, an inhibitor of the NF-kB-mediated anti-apoptotic pathway. By inhibiting the NF-kB signaling pathway, we hypothesized that increased NFKBIA would promote TNF-stimulated cell death, and was confirmed by rescuing colonic epithelial cell phenotype in Mettl14 deficient mice via using TNF inhibition. Taken together, we identify a novel role of m6A modification in normal colonic epithelial cell development by regulating NF-κB-mediated anti-apoptotic pathway.

— Written by Dr. Chenbo Ding in Mar, 2022