小柯机器人

法国巴黎文理研究大学Deborah Bourc’his、Tomasz Chelmicki等研究人员合作发现，m⁶A RNA甲基化调节内源性逆转录病毒的命运。相关论文于2021年1月13日在线发表在《自然》杂志上。

通过在小鼠胚胎干细胞中使用基因组规模的无偏CRISPR基因敲除筛选，研究人员确定m⁶A RNA甲基化是一种限制内源性逆转录病毒（ERV）的方法。ERV mRNA的甲基化被甲基转移酶样METTL3–METTL14蛋白复合物所催化，研究人员发现METTL3–METTL14及其辅助亚基WTAP和ZC3H13的敲低能够特异性导致脑池内A颗粒（IAP）mRNA丰度和相关ERVK元件的增加，这是通过靶向其5'非翻译区域来实现的。

通过使用受调控的生长素依赖型METTL3–METTL14酶复合物降解，研究人员发现IAP mRNA和蛋白质丰度与m⁶A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，研究人员发现m⁶A甲基化主要是通过降低IAP mRNA的半衰期起作用的，这是通过募集mTHA阅读器蛋白YTHDF家族而发生的。总之，这些结果表明，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，并且这在转录沉默不太严格时尤其重要。

据了解，ERV是大量且异源的整合逆转录病毒序列，它们在以RNA为中心的整个生命周期中影响基因组调控和细胞生理。ERV的抑制失败与癌症、不育、衰老和神经退行性疾病相关。

附：英文原文

Title: m 6 A RNA methylation regulates the fate of endogenous retroviruses

Author: Tomasz Chelmicki, Emeline Roger, Aurlie Teissandier, Mathilde Dura, Lorraine Bonneville, Sofia Rucli, Franois Dossin, Camille Fouassier, Sonia Lameiras, Deborah Bourchis

Issue&Volume: 2021-01-13

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.

DOI: 10.1038/s41586-020-03135-1

Source: https://www.nature.com/articles/s41586-020-03135-1

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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