Journal
NATURE
Volume 591, Issue 7849, Pages 312-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-020-03135-1
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Funding
- Agence Nationale de la Recherche [ANR-10-EQPX-03, ANR-10-INBS-09-08]
- Cell and Tissue Imaging Platform (PICT-IBiSA) of Institut Curie of the French National Research Infrastructure France-BioImaging [ANR-10-INBS-04]
- LABEX DEEP [ANR-11-LABX-0044, ANR-10-IDEX-0001-02]
- Fondation Bettencourt Schueller
- Association Robert Debre pour la Recherche Medicale (ARDRM)
- Fondation pour la Recherche Medicale (FRM)
- Association de Recherche contre le Cancer [ARC-PJA-20191209637]
- EMBO postdoctoral fellowship
- la Ligue contre le Cancer
- Region Ile-de-France
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Research indicates that m(6)A RNA methylation can restrict ERVs, maintaining cellular integrity by reducing the half-life of IAP mRNA to clear reactive ERV-derived RNA species.
Endogenous retroviruses (ERVs) are abundant and heterogenous groups of integrated retroviral sequences that affect genome regulation and cell physiology throughout their RNA-centred life cycle(1). Failure to repress ERVs is associated with cancer, infertility, senescence and neurodegenerative diseases(2,3). Here, using an unbiased genome-scale CRISPR knockout screen in mouse embryonic stem cells, we identify m(6)A RNA methylation as a way to restrict ERVs. Methylation of ERV mRNAs is catalysed by the complex of methyltransferase-like METTL3-METTL14(4) 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 m(6)A catalysis. By monitoring chromatin states and mRNA stability upon METTL3-METTL14 double depletion, we found that m(6)A methylation mainly acts by reducing the half-life of IAP mRNA, and this occurs by the recruitment of the YTHDF family of m(6)A reader proteins(5). 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.
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