The U6 snRNA m6A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention

Cell. 2017 May 18;169(5):824-835.e14. doi: 10.1016/j.cell.2017.05.003.


Maintenance of proper levels of the methyl donor S-adenosylmethionine (SAM) is critical for a wide variety of biological processes. We demonstrate that the N6-adenosine methyltransferase METTL16 regulates expression of human MAT2A, which encodes the SAM synthetase expressed in most cells. Upon SAM depletion by methionine starvation, cells induce MAT2A expression by enhanced splicing of a retained intron. Induction requires METTL16 and its methylation substrate, a vertebrate conserved hairpin (hp1) in the MAT2A 3' UTR. Increasing METTL16 occupancy on the MAT2A 3' UTR is sufficient to induce efficient splicing. We propose that, under SAM-limiting conditions, METTL16 occupancy on hp1 increases due to inefficient enzymatic turnover, which promotes MAT2A splicing. We further show that METTL16 is the long-unknown methyltransferase for the U6 spliceosomal small nuclear RNA (snRNA). These observations suggest that the conserved U6 snRNA methyltransferase evolved an additional function in vertebrates to regulate SAM homeostasis.

Keywords: Intron retention; MAT2A; METTL16; N6-methyladenosine (m(6)A); RNA methylation; S-adenosylmethionine (SAM); SAM metabolism; U6 snRNA; alternative splicing; methionine.

MeSH terms

  • Animals
  • Base Sequence
  • Gene Expression Regulation, Enzymologic
  • HEK293 Cells
  • Humans
  • Introns*
  • Inverted Repeat Sequences
  • Methionine Adenosyltransferase / chemistry
  • Methionine Adenosyltransferase / genetics*
  • Methylation
  • Methyltransferases / chemistry
  • Methyltransferases / metabolism*
  • RNA Splicing*
  • S-Adenosylmethionine / metabolism*
  • Schizosaccharomyces / metabolism


  • S-Adenosylmethionine
  • METTL16 protein, human
  • Methyltransferases
  • U6 small nuclear RNA methyltransferase
  • MAT2A protein, human
  • Methionine Adenosyltransferase