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

Mol Cell. 2018 Sep 20;71(6):986-1000.e11. doi: 10.1016/j.molcel.2018.08.004. Epub 2018 Sep 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Animals
  • Demethylation
  • Embryonic Development / genetics
  • Embryonic Development / physiology
  • Gene Expression / genetics
  • HEK293 Cells
  • Humans
  • Methionine Adenosyltransferase
  • Methylation
  • Methyltransferases / metabolism*
  • Methyltransferases / physiology
  • Methyltransferases / ultrastructure*
  • Mice / embryology
  • Mice, Knockout
  • RNA
  • RNA Processing, Post-Transcriptional / physiology
  • RNA, Messenger / metabolism
  • RNA, Small Nuclear / metabolism


  • RNA, Messenger
  • RNA, Small Nuclear
  • U6 small nuclear RNA
  • RNA
  • N-methyladenosine
  • METTL16 protein, human
  • Methyltransferases
  • Mettl3 protein, mouse
  • MAT2A protein, human
  • Methionine Adenosyltransferase
  • Adenosine