m6A RNA methylation regulates the fate of endogenous retroviruses

Tomasz Chelmicki (), Emeline Roger, Aurélie Teissandier, Mathilde Dura, Lorraine Bonneville, Sofia Rucli, François Dossin, Camille Fouassier, Sonia Lameiras and Deborah Bourc’his ()
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Tomasz Chelmicki: Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215
Emeline Roger: Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215
Aurélie Teissandier: Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215
Mathilde Dura: Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215
Lorraine Bonneville: Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215
Sofia Rucli: Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215
François Dossin: European Molecular Biology Laboratory
Camille Fouassier: CRISPR’IT Genetic Platform Screening, Institut Curie
Sonia Lameiras: PSL Research University
Deborah Bourc’his: Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215

Nature, 2021, vol. 591, issue 7849, 312-316

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-020-03135-1

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