CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China.
Nature. 2021 Mar;591(7849):322-326. doi: 10.1038/s41586-021-03313-9. Epub 2021 Mar 3.
The RNA modification N-methyladenosine (mA) has critical roles in many biological processes. However, the function of mA in the early phase of mammalian development remains poorly understood. Here we show that the mA reader YT521-B homology-domain-containing protein 1 (YTHDC1) is required for the maintenance of mouse embryonic stem (ES) cells in an mA-dependent manner, and that its deletion initiates cellular reprogramming to a 2C-like state. Mechanistically, YTHDC1 binds to the transcripts of retrotransposons (such as intracisternal A particles, ERVK and LINE1) in mouse ES cells and its depletion results in the reactivation of these silenced retrotransposons, accompanied by a global decrease in SETDB1-mediated trimethylation at lysine 9 of histone H3 (H3K9me3). We further demonstrate that YTHDC1 and its target mA RNAs act upstream of SETDB1 to repress retrotransposons and Dux, the master inducer of the two-cell stage (2C)-like program. This study reveals an essential role for mA RNA and YTHDC1 in chromatin modification and retrotransposon repression.
RNA 修饰 N6-甲基腺苷（m6A）在许多生物学过程中具有关键作用。然而，m6A 在哺乳动物早期发育阶段的功能仍知之甚少。本文中，作者发现 m6A 读蛋白 YT521-B 同源结构域蛋白 1（YTHDC1）以 m6A 依赖的方式维持小鼠胚胎干细胞（ES 细胞），其缺失会引发细胞重编程为 2C 样状态。机制上，YTHDC1 与小鼠 ES 细胞中转座子（如内顺式 A 颗粒、ERVK 和 LINE1）的转录本结合，其耗竭导致这些沉默的转座子被重新激活，同时 SETDB1 介导的组蛋白 H3 赖氨酸 9 三甲基化（H3K9me3）水平全局下降。作者进一步证明，YTHDC1 及其靶 m6A RNA 在上游调控 SETDB1 以抑制转座子和 Dux，后者是 2C 样程序的两细胞阶段（2C）主诱导因子。该研究揭示了 m6A RNA 和 YTHDC1 在染色质修饰和转座子抑制中的重要作用。
