Methylation of Structured RNA by the m6A Writer METTL16 Is Essential for Mouse Embryonic Development

Abstract

Internal modification of RNAs with N⁶-methyladenosine (m⁶A) is a highly conserved means of gene expression control. While the METTL3/METTL14 heterodimer adds this mark on thousands of transcripts in a single-stranded context, the substrate requirements and physiological roles of the second m⁶A writer METTL16 remain unknown. Here we describe the crystal structure of human METTL16 to reveal a methyltransferase domain furnished with an extra N-terminal module, which together form a deep-cut groove that is essential for RNA binding. When presented with a random pool of RNAs, METTL16 selects for methylation-structured RNAs where the critical adenosine is present in a bulge. Mouse 16-cell embryos lacking Mettl16 display reduced mRNA levels of its methylation target, the SAM synthetase Mat2a. The consequence is massive transcriptome dysregulation in ∼64-cell blastocysts that are unfit for further development. This highlights the role of an m⁶A RNA methyltransferase in facilitating early development via regulation of SAM availability.

Keywords: METTL16; Mat2a; SAM availability; SAM synthetase; U6 snRNA; blastocysts; crystal structure; m(6)A; morula; splicing.