N⁶-adenomethylation of GsdmC is essential for Lgr5⁺ stem cell survival to maintain normal colonic epithelial morphogenesis.

ABSTRACT: Gut epithelial morphogenesis is maintained by intestinal stem cells. Here, we report that depletion of N⁶-adenosine methyltransferase subunit Mettl14 from gut epithelial cells in mice impaired colon mucosal morphogenesis, leading to increased mucosal permeability, severe inflammation, growth retardation, and premature death. Mettl14 ablation triggered apoptosis that depleted Lgr5⁺ stem cells and disrupted colonic organoid growth and differentiation, whereas the inhibition of apoptosis rescued Mettl14-deleted mice and organoids. Mettl14 depletion disrupted N⁶-adenomethylation on GsdmC transcripts and abolished GsdmC expression. Reconstitution of Mettl14-deleted organoids or mice with GSDMC rescued Lgr5 expression and prevented apoptosis and mouse premature d

SUBMITTER: Du J 

PROVIDER: S-EPMC9398964 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature