Methylation of structured RNA by the m6A writer METTL16 is essential for mouse embryonic development

Internal modification of RNAs with N6-methyladenosine (m6A) is a highly conserved and widely used means of gene expression control. METTL16 is an m6A writer but how it recognizes its RNA targets and its physiological roles remain unknown. Here we describe the crystal structure of human METTL16 to reveal a classical methyltransferase domain but with an extra N-terminal module that is essential for catalysis. Together, they form a deep-cut groove lined by highly conserved positively charged residues that are essential for RNA binding and methylation activity. When given a random pool of RNAs, METTL16 selects structured RNAs for m6A methylation. We demonstrate that mouse Mettl16 is essential for early embryonic development, and acts via regulation of the SAM synthetase Mat2a mRNA. Our results highlight the pivotal role of an m6A RNA methyltransferase in facilitating early developmental decisions via regulation of SAM availability.