2. Academic Validation
  3. Methylation of Structured RNA by the m6A Writer METTL16 Is Essential for Mouse Embryonic Development

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.
Mateusz Mendel 1,  Kuan-Ming Chen 1,  David Homolka 1,  Pascal Gos 1,  Radha Raman Pandey 1,  Andrew A McCarthy 2,  Ramesh S Pillai 3
Affiliations

Affiliations

  • 1 Department of Molecular Biology, Science III, University of Geneva, 30 Quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland.
  • 2 European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, 38042 Grenoble, France.
  • 3 Department of Molecular Biology, Science III, University of Geneva, 30 Quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland. Electronic address: ramesh.pillai@unige.ch.
PMID: 30197299 DOI: 10.1016/j.molcel.2018.08.004
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.

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