Segregation of the stemness program from the proliferation program in intestinal stem cells

Stem cells can undergo continuous self-renewal and meanwhile retain the stemness capability to differentiate to mature functional cells. However, it is unclear whether the proliferation property can be segregated from the stemness in stem cells. The intestinal epithelium undergoes fast renewal, and the Lgr5+ intestinal stem cells (ISCs) are essential to maintain homeostasis. Here, we report that methyltransferase-like 3 (Mettl3), a critical enzyme for N6-methyladenosine (m6A) methylation, is required for ISCs maintenance as its deletion results in fast loss of stemness markers but has no effect on cell proliferation. We further identify four m6A-modified transcriptional factors, whose ectopic expression can restore stemness gene expression in Mettl3-/- organoids, while their silencing leads to stemness loss. In addition, transcriptomic profiling analysis discerns 23 genes that can be segregated from the genes responsible for cell proliferation. Together, these data reveal that m6A modification sustains ISC stemness, which can be uncoupled from cell proliferation.

Automated summary

This study reveals the critical role of methyltransferase-like 3 (Mettl3) in maintaining intestinal stem cell (ISC) stemness through N6-methyladenosine (m6A) methylation, independent of cell proliferation. The researchers identified four m6A-modified transcription factors that can restore stemness gene expression in Mettl3-deficient organoids, and also discerned 23 genes unrelated to cell proliferation. These findings demonstrate the importance of m6A modification in sustaining ISC stemness and its uncoupling from cell proliferation.