m6A RNA methylation regulates the fate of endogenous retroviruses

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 diseases^2,3. 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.