Human METTL16 is a N6-methyladenosine (m6A) methyltransferase that targets pre-mRNAs and various non-coding RNAs

EMBO Rep. 2017 Nov;18(11):2004-2014. doi: 10.15252/embr.201744940. Epub 2017 Oct 19.


N6-methyladenosine (m6A) is a highly dynamic RNA modification that has recently emerged as a key regulator of gene expression. While many m6A modifications are installed by the METTL3-METTL14 complex, others appear to be introduced independently, implying that additional human m6A methyltransferases remain to be identified. Using crosslinking and analysis of cDNA (CRAC), we reveal that the putative human m6A "writer" protein METTL16 binds to the U6 snRNA and other ncRNAs as well as numerous lncRNAs and pre-mRNAs. We demonstrate that METTL16 is responsible for N6-methylation of A43 of the U6 snRNA and identify the early U6 biogenesis factors La, LARP7 and the methylphosphate capping enzyme MEPCE as METTL16 interaction partners. Interestingly, A43 lies within an essential ACAGAGA box of U6 that base pairs with 5' splice sites of pre-mRNAs during splicing, suggesting that METTL16-mediated modification of this site plays an important role in splicing regulation. The identification of METTL16 as an active m6A methyltransferase in human cells expands our understanding of the mechanisms by which the m6A landscape is installed on cellular RNAs.

Keywords: N6‐methyladenosine (m(6)A); RNA modification; methyltransferase; pre‐mRNA splicing; snRNA.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Base Pairing
  • Base Sequence
  • DNA, Complementary / genetics
  • DNA, Complementary / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Methylation
  • Methyltransferases / genetics*
  • Methyltransferases / metabolism
  • Oligopeptides / genetics
  • Oligopeptides / metabolism
  • RNA Precursors / genetics*
  • RNA Precursors / metabolism
  • RNA Splicing*
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Nuclear / genetics
  • RNA, Small Nuclear / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Ribonucleoproteins / genetics
  • Ribonucleoproteins / metabolism


  • DNA, Complementary
  • Larp7 protein, human
  • MALAT1 long non-coding RNA, human
  • Oligopeptides
  • RNA Precursors
  • RNA, Long Noncoding
  • RNA, Messenger
  • RNA, Small Nuclear
  • Recombinant Fusion Proteins
  • Ribonucleoproteins
  • U6 small nuclear RNA
  • Green Fluorescent Proteins
  • FLAG peptide
  • N-methyladenosine
  • METTL16 protein, human
  • MePCE protein, human
  • Methyltransferases
  • Adenosine

Associated data

  • GENBANK/NM_024086.3