The 18S rRNA m6A methyltransferase METTL5 promotes mouse embryonic stem cell differentiation

RNA modifications represent a novel layer of regulation of gene expression. Functional experiments revealed that N6-methyladenosine (m6A) on messenger RNA (mRNA) plays critical roles in cell fate determination and development. The m6A mark also resides in the decoding center of 18S ribosomal RNA (rRNA), however, the biological function of m6A on 18S rRNA is still poorly understood. Here, we report that methyltransferase-like 5 (METTL5) methylates 18S rRNA both in vivo and in vitro, which is consistent with previous reports. Deletion of Mettl5 causes a dramatic differentiation defect in mouse embryonic stem cells (mESCs). Mechanistically, m6A deposited by METTL5 regulates the efficient translation of F-box and WD repeat domain-containing 7 (FBXW7), a key regulator of cell differentiation. Deficiency of METTL5 reduces FBXW7 levels and leads to the accumulation of its substrate c-MYC, thereby delaying the onset of mESC differentiation. Our study uncovers an important role of METTL5-mediated 18S m6A in mESC differentiation through translation regulation and provides new insight into the functional significance of rRNA m6A.