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 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.

journal_name

Nature

journal_title

Nature

authors

Chelmicki T,Roger E,Teissandier A,Dura M,Bonneville L,Rucli S,Dossin F,Fouassier C,Lameiras S,Bourc'his D

doi

10.1038/s41586-020-03135-1

subject

Has Abstract

pub_date

2021-01-13 00:00:00

eissn

0028-0836

issn

1476-4687

pii

10.1038/s41586-020-03135-1

pub_type

杂志文章

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