m6A RNA methylation regulates the fate of endogenous retroviruses

Nature. 2021 Mar;591(7849):312-316. doi: 10.1038/s41586-020-03135-1. Epub 2021 Jan 13.

Abstract

Endogenous retroviruses (ERVs) are abundant and heterogenous groups of integrated retroviral sequences that affect genome regulation and cell physiology throughout their RNA-centred life cycle1. Failure to repress ERVs is associated with cancer, infertility, senescence and neurodegenerative diseases2,3. Here, using an unbiased genome-scale CRISPR knockout screen in mouse embryonic stem cells, we identify m6A RNA methylation as a way to restrict ERVs. Methylation of ERV mRNAs is catalysed by the complex of methyltransferase-like METTL3-METTL144 proteins, and we found that depletion of METTL3-METTL14, along with their accessory subunits WTAP and ZC3H13, led to increased mRNA abundance of intracisternal A-particles (IAPs) and related ERVK elements specifically, by targeting their 5' untranslated region. Using controlled auxin-dependent degradation of the METTL3-METTL14 enzymatic complex, we showed that IAP mRNA and protein abundance is dynamically and inversely correlated with m6A catalysis. By monitoring chromatin states and mRNA stability upon METTL3-METTL14 double depletion, we found that m6A methylation mainly acts by reducing the half-life of IAP mRNA, and this occurs by the recruitment of the YTHDF family of m6A reader proteins5. Together, our results indicate that RNA methylation provides a protective effect in maintaining cellular integrity by clearing reactive ERV-derived RNA species, which may be especially important when transcriptional silencing is less stringent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems / genetics
  • Cell Cycle Proteins / metabolism
  • Chromatin / chemistry
  • Chromatin / genetics
  • Chromatin / metabolism
  • Endogenous Retroviruses / genetics*
  • Gene Knockout Techniques
  • Genes, Intracisternal A-Particle / genetics*
  • Half-Life
  • Methylation*
  • Methyltransferases / metabolism
  • Mice
  • Mouse Embryonic Stem Cells
  • Nuclear Proteins / metabolism
  • RNA Splicing Factors / metabolism
  • RNA Stability
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • Chromatin
  • Nuclear Proteins
  • RNA Splicing Factors
  • RNA, Messenger
  • RNA-Binding Proteins
  • Wtap protein, mouse
  • Ythdf1 protein, mouse
  • Zc3h13 protein, mouse
  • 6-methyladenine mRNA methyltransferase
  • Methyltransferases
  • Mettl14 protein, mouse
  • Mettl3 protein, mouse