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m 6 A RNA methylation regulates the fate of endogenous retroviruses
Nature ( IF 42.778 ) Pub Date : 2021-01-13 , DOI: 10.1038/s41586-020-03135-1
Tomasz Chelmicki; Emeline Roger; Aurélie Teissandier; Mathilde Dura; Lorraine Bonneville; Sofia Rucli; François Dossin; Camille Fouassier; Sonia Lameiras; Deborah Bourc’his

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.



中文翻译:

m 6 RNA甲基化调节内源性逆转录病毒的命运

内源性逆转录病毒(ERV)是大量且异源的整合逆转录病毒序列,它们在整个以RNA为中心的生命周期中影响基因组调控和细胞生理1。未能抑制ERVs与癌症,不孕症,衰老和神经退行性疾病2,3有关。在这里,在小鼠胚胎干细胞中使用无偏见的基因组规模的CRISPR基因敲除筛选,我们确定m 6 A RNA甲基化是一种限制ERV的方法。ERV mRNA的甲基化由类似于甲基转移酶的METTL3–METTL14 4催化。蛋白质,我们发现METTL3–METTL14及其辅助亚基WTAP和ZC3H13的耗竭,通过靶向5'非翻译区,导致了脑内核内A颗粒(IAP)和相关ERVK元件的mRNA丰度增加。使用METTL3–METTL14酶促复合物的受控生长素依赖性降解,我们表明IAP mRNA和蛋白丰度与m 6 A催化动力学相关且呈负相关。通过监测METTL3–METTL14双耗竭时的染色质状态和mRNA稳定性,我们发现m 6 A甲基化主要是通过降低IAP mRNA的半衰期起作用的,这是由于募集了YTHDF m 6 A阅读器蛋白家族5。总之,我们的结果表明,RNA甲基化可通过清除反应性ERV衍生的RNA种类来提供维持细胞完整性的保护作用,这在转录沉默不太严格时尤其重要。

更新日期:2021-01-13
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