The 18S rRNA m⁶ A 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 (m⁶ A) on messenger RNA (mRNA) plays critical roles in cell fate determination and development. m⁶ A mark also resides in the decoding center of 18S ribosomal RNA (rRNA); however, the biological function of m⁶ A 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, the m⁶ A deposited by METTL5 is involved in regulating 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 m⁶ A in mESC differentiation through translation regulation and provides new insight into the functional significance of rRNA m⁶ A.