m⁶A mRNA modification maintains colonic epithelial cell homeostasis via NF-κB-mediated antiapoptotic pathway.

Abstract

Colonic mucosal barrier dysfunction is one of the major causes of inflammatory bowel disease (IBD). However, the mechanisms underlying mucosal barrier dysfunction are poorly understood. <i>N</i>⁶-methyladenosine (m⁶A) mRNA modification is an important modulator of epitranscriptional regulation of gene expression, participating in multiple physiological and pathological processes. However, the function of m⁶A modification in colonic epithelial cells and stem cells is unknown. Here, we show that m⁶A modification is essential for maintaining the homeostatic self-renewal in colonic stem cells. Specific deletion of the methyltransferase 14 (<i>Mettl14</i>) gene in mouse colon resulted in colonic stem cell apoptosis, causing mucosal barrier dysfunction and severe colitis. Mechanistically, we revealed that <i>Mettl14</i> restricted colonic epithelial cell death by regulating the stability of <i>Nfkbia</i> mRNA and modulating the NF-κB pathway. Our results identified a previously unidentified role for m⁶A modification in colonic epithelial cells and stem cells, suggesting that m⁶A modification may be a potential therapeutic target for IBD.