The 18S rRNA m 6 A methyltransferase METTL 5 promotes mouse embryonic stem cell differentiation

RNA modifications represent a novel layer of regulation of gene expression. Functional experiments revealed that N 6 ‐methyladenosine (m 6 A) on messenger RNA ( mRNA ) plays critical roles in cell fate determination and development. m 6 A mark also resides in the decoding center of 18S ribosomal RNA ( rRNA ); however, the biological function of m 6 A on 18S rRNA is still poorly understood. Here, we report that methyltransferase‐like 5 ( METTL 5) 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 ( mESC s). Mechanistically, the m 6 A deposited by METTL 5 is involved in regulating the efficient translation of F‐box and WD repeat domain‐containing 7 ( FBXW 7), a key regulator of cell differentiation. Deficiency of METTL 5 reduces FBXW 7 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 METTL 5‐mediated 18S m 6 A in mESC differentiation through translation regulation and provides new insight into the functional significance of rRNA m 6 A.