METTL3 counteracts premature aging via m(6)A-dependent stabilization of MIS12 mRNA

N(6)-Methyladenosine (m(6)A) messenger RNA methylation is a well-known epitranscriptional regulatory mechanism affecting central biological processes, but its function in human cellular senescence remains uninvestigated. Here, we found that levels of both m(6)A RNA methylation and the methyltransferase METTL3 were reduced in prematurely senescent human mesenchymal stem cell (hMSC) models of progeroid syndromes. Transcriptional profiling of m(6)A modifications further identified MIS12, for which m(6)A modifications were reduced in both prematurely senescent hMSCs and METTL3-deficient hMSCs. Knockout of METTL3 accelerated hMSC senescence whereas overexpression of METTL3 rescued the senescent phenotypes. Mechanistically, loss of m(6)A modifications accelerated the turnover and decreased the expression of MIS12 mRNA while knockout of MIS12 accelerated cellular senescence. Furthermore, m(6)A reader IGF2BP2 was identified as a key player in recognizing and stabilizing m(6)A-modified MIS12 mRNA. Taken together, we discovered that METTL3 alleviates hMSC senescence through m(6)A modification-dependent stabilization of the MIS12 transcript, representing a novel epitranscriptional mechanism in premature stem cell senescence.