小柯机器人

复旦大学沈宏杰和施扬研究组合作取得一项新成果。他们的最新研究揭示METTL3（类似于甲基转移酶3）调节小鼠胚胎干细胞中的异染色质。2021年1月27日，《自然》杂志发表了这一成果。

他们显示METTL3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。METTL3主要定位于内源性逆转录病毒的脑池内A颗粒（IAP）型家族。敲除Mettl3会损害多个异染色质标记在METTL3靶向的IAP上的分布，并上调IAP转录，这表明METTL3对于IAP异染色质的完整性很重要。

他们提供了进一步的证据，证明与METTL3结合的IAP来源的RNA转录本与染色质相关，并且被N6-甲基腺苷（m6A）-甲基化。这些m6A标记的转录本受m6A阅读器YTHDC1的束缚，后者与METTL3相互作用，进而促进METTL3与染色质的缔合。 METTL3还与组蛋白3赖氨酸9（H3K9）三甲基转移酶SETDB1及其辅因子TRIM28发生物理相互作用，并且对于它们向IAP的定位至关重要。他们的发现表明，METTL3催化的m6A RNA修饰对于小鼠胚胎干细胞中IAP异染色质的完整性很重要，揭示了哺乳动物中异染色质调节的机制。

据悉，METTL3介导mRNA的m6A甲基化，这会影响mRNA的稳定性及其向蛋白质的翻译。METTL3也结合染色质，但尚未完全理解METTL3和m6A甲基化在染色质中的作用。

附：英文原文

Title: METTL3 regulates heterochromatin in mouse embryonic stem cells

Author: Wenqi Xu, Jiahui Li, Chenxi He, Jing Wen, Honghui Ma, Bowen Rong, Jianbo Diao, Liyong Wang, Jiahua Wang, Feizhen Wu, Li Tan, Yujiang Geno Shi, Yang Shi, Hongjie Shen

Issue&Volume: 2021-01-27

Abstract: METTL3 (methyltransferase-like 3) mediates the N6-methyladenosine (m6A) methylation of mRNA, which affects the stability of mRNA and its translation into protein1. METTL3 also binds chromatin2,3,4, but the role of METTL3 and m6A 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 development5. 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 m6A-methylated. These m6A-marked transcripts are bound by the m6A 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 m6A modification of RNA is important for the integrity of IAP heterochromatin in mouse embryonic stem cells, revealing a mechanism of heterochromatin regulation in mammals.

DOI: 10.1038/s41586-021-03210-1

Source: https://www.nature.com/articles/s41586-021-03210-1

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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