m 6 A RNA methylation regulates the fate of endogenous retroviruses

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.