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

• DOI: 10.15252/embr.201949863
• Publication Date: 2020-08-12T06:13:55Z
• Authors: Ming Xing; Qi Liu; Cong Mao; Hanyi Zeng; Xin Zhang; Shuqin Zhao; Li Chen; Mingxi Liu; Bin Shen; Xuejiang Guo; Honghui Ma; Hao Chen; Jun Zhang
• Keywords: Embryology

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.