m6A RNA methylation regulates the fate of endogenous retroviruses
m6A RNA methylation regulates the fate of endogenous retroviruses
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DOI：
10.1038/s41586-020-03135-1
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发表时间：
2021-01-13
期刊：
影响因子：
64.8
通讯作者：
Bourc'his, Deborah
中科院分区：
文献类型：
--
作者：
Chelmicki, Tomasz;Roger, Emeline;Bourc'his, Deborah
内源性逆转录病毒(ERV)是一组丰富的异源整合逆转录病毒序列，在其以RNA为中心的生命周期中影响基因组调节和细胞生理[1]。未能抑制ERV与癌症、不孕、衰老和神经退行性疾病有关(2，3)。在这里，在小鼠胚胎干细胞中使用无偏见的基因组规模CRISPR基因敲除筛查，我们确定m(6)A RNA甲基化是限制ERV的一种方法。ERV mRNAs的甲基化是由甲基转移酶样蛋白METTL3-METTL14(4)的复合体催化的，我们发现METTL3-METTL14及其附属亚单位WTAP和ZC3H13的缺失通过靶向A粒子(IAPs)和相关ERVK元件的5‘非翻译区特异性地增加了IAPs和相关ERVK元件的mRNA丰度。通过对METTL3-METTL14酶复合体进行生长素依赖的受控降解，我们发现IAP mRNA和蛋白丰度与m(6)A催化作用呈动态负相关。通过监测染色质状态和对METTL3-METTL14双缺失的mRNA稳定性，我们发现m(6)A甲基化主要通过减少IAP mRNA的半衰期起作用，这是通过招募YTHDF家族的m(6)A阅读器蛋白(5)发生的。综上所述，我们的结果表明，RNA甲基化通过清除反应性ERV衍生的RNA物种在维持细胞完整性方面提供了一种保护作用，当转录沉默不那么严格时，这一点可能特别重要。
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.