Mettl14 is required for mouse postimplantation development by facilitating epiblast maturation

N6-methyladenosine (m6A) is the most prevalent and reversible internal modification of mammalian messenger and noncoding RNAs mediated by specificm6A writer, reader, and eraser proteins. As an m6A writer, the methyltransferase-like 3-methyltransferase–like 14 (METTL14)–Wilms tumor 1–associated protein complex dynamically regulates m6A modification and plays important roles in diverse biologic processes. However, our knowledge about the complete functions of this RNA methyltransferase complex, the contributions of each componenttothemethylation, andtheir effects on different biologicpathways are still limited. By using both in vivo and in vitro models, we here report that METTL14 is indispensable for postimplantation embryonic development by facilitating the conversion from naive to primed state of the epiblast. Depletion of Mettl14 leads to conspicuous embryonic growth retardation from embryonic d 6.5, mainly as a result of resistanceto differentiation, which further leads to embryonic lethality early in gestation. Our data highlight the critical function of METTL14 as an m6A modification regulator in orchestrating early mouse embryogenesis. To investigate the molecular consequences of Mettl14 depletion in mouse early embryogenesis, we isolated mRNA from control and Mettl142/2 embryos at E5.5 and performed RNA sequencing. We chose E5.5 mouse embryos because the mutant embryos at this stage were not distinguishable in morphology from normal littermates, thus minimizing molecular changes ascribed to secondary developmental defects in the absence ofMETTL14.