METTL3 regulates heterochromatin in mouse embryonic stem cells
METTL3 regulates heterochromatin in mouse embryonic stem cells
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METTL3 调节小鼠胚胎干细胞中的异染色质
DOI：
10.1038/s41586-021-03210-1
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发表时间：
2021-01-27
期刊：
影响因子：
64.8
通讯作者：
Shen, Hongjie
中科院分区：
文献类型：
--
作者：
Xu, Wenqi;Li, Jiahui;Shen, Hongjie
胃L3（甲基转移酶样3）介导mRNA的N-6-甲基腺苷（m（6）A）甲基化，其影响mRNA的稳定性及其翻译成蛋白质（1）。胃L3也结合染色质（2-4），但胃L3和m（6）A甲基化在染色质中的作用尚未完全了解。在这里，我们表明，胃L3调节小鼠胚胎干细胞异染色质，其完整性对于沉默逆转录病毒元件和哺乳动物发育至关重要（5）。囊L3主要定位于内源性逆转录病毒的脑池内A颗粒（IAP）型家族。Mettl 3的敲除削弱了多个异染色质标记物在胃L3靶向的IAP上的沉积，并上调IAP转录，表明胃L3对于IAP异染色质的完整性是重要的。我们提供了进一步的证据，证明来自与胃L3结合的IAP的RNA转录物与染色质相关，并且是m（6）A-甲基化的。这些m（6）A标记的转录物与m（6）A阅读器YTHDC 1结合，YTHDC 1与胃L3相互作用，进而促进胃L3与染色质的结合。胃L3还与组蛋白3赖氨酸9（H3 K9）三甲基转移酶SETDB 1及其辅因子TRIM 28物理相互作用，并且对于它们定位于IAP是重要的。我们的研究结果表明，α-L3催化的m（6）RNA的A修饰对于小鼠胚胎干细胞中IAP异染色质的完整性非常重要，揭示了哺乳动物异染色质调节的机制。
METTL3 (methyltransferase-like 3) mediates the N-6-methyladenosine (m(6)A) methylation of mRNA, which affects the stability of mRNA and its translation into protein(1). METTL3 also binds chromatin(2-4), but the role of METTL3 and m(6)A methylation in chromatin is not fully understood. Here we show that METTL3 regulates mouse embryonic stem-cell heterochromatin, the integrity of which is critical for silencing retroviral elements and for mammalian development(5). METTL3 predominantly localizes to the intracisternal A particle (IAP)-type family of endogenous retroviruses. Knockout of Mettl3 impairs the deposition of multiple heterochromatin marks onto METTL3-targeted IAPs, and upregulates IAP transcription, suggesting that METTL3 is important for the integrity of IAP heterochromatin. We provide further evidence that RNA transcripts derived from METTL3-bound IAPs are associated with chromatin and are m(6)A-methylated. These m(6)A-marked transcripts are bound by the m(6)A reader YTHDC1, which interacts with METTL3 and in turn promotes the association of METTL3 with chromatin. METTL3 also interacts physically with the histone 3 lysine 9 (H3K9) tri-methyltransferase SETDB1 and its cofactor TRIM28, and is important for their localization to IAPs. Our findings demonstrate that METTL3-catalysed m(6)A modification of RNA is important for the integrity of IAP heterochromatin in mouse embryonic stem cells, revealing a mechanism of heterochromatin regulation in mammals.