美国哈佛医学院Mo Motamedi团队近期取得重要工作进展，他们研究提出，RNA质量控制因子使Clr4/SUV39H成核并触发组成型异染色质组装。相关研究成果2024年5月29日在线发表于《细胞》杂志上。
据介绍，在真核生物中，Suv39蛋白家族使组蛋白H3的第9位赖氨酸发生三甲基化（H3K9me3），形成组成型异染色质。然而，Suv39蛋白如何在异染色质上成核尚不完全清楚。在裂变酵母中，目前的模型假设Argonaut1相关的小RNA（sRNA）将唯一的H3K9甲基转移酶Clr4/SUV39H成核到着丝粒。
研究人员发现，在不存在所有sRNA和H3K9me的情况下，Mtl1和Red1核心（MTREC）/PEXT复合物在异染色质长链非编码RNA（lncRNA）处使Clr4/SUV39H成核，在该异色长不编码RNA处，两种H3K9脱乙酰酶Sir2和Clr3也通过不同的机制积累。H3K9去乙酰化和甲基化的迭代循环以一种独立于sRNA的方式，将Clr4/SUV39H从成核中心扩散开来，产生一种基础H3K9me状态。RNAi机制利用这种状态来增强和扩大中心粒上的Clr4/H3K9me信号，从而建立异染色质。
总之，这一研究揭示出lncRNA和RNA质量控制因子可以在真核生物中，核化异染色质并发挥表观遗传沉默子的功能。
附：英文原文
Title: RNA quality control factors nucleate Clr4/SUV39H and trigger constitutive heterochromatin assembly
Author: Jasbeer S. Khanduja, Richard I. Joh, Monica M. Perez, Joao A. Paulo, Christina M. Palmieri, Jingyu Zhang, Alex O.D. Gulka, Willhelm Haas, Steven P. Gygi, Mo Motamedi
Issue&Volume: 2024-05-29
Abstract: In eukaryotes, the Suv39 family of proteins tri-methylate lysine 9 of histone H3 (H3K9me) to form constitutive heterochromatin. However, how Suv39 proteins are nucleated at heterochromatin is not fully described. In the fission yeast, current models posit that Argonaute1-associated small RNAs (sRNAs) nucleate the sole H3K9 methyltransferase, Clr4/SUV39H, to centromeres. Here, we show that in the absence of all sRNAs and H3K9me, the Mtl1 and Red1 core (MTREC)/PAXT complex nucleates Clr4/SUV39H at a heterochromatic long noncoding RNA (lncRNA) at which the two H3K9 deacetylases, Sir2 and Clr3, also accumulate by distinct mechanisms. Iterative cycles of H3K9 deacetylation and methylation spread Clr4/SUV39H from the nucleation center in an sRNA-independent manner, generating a basal H3K9me state. This is acted upon by the RNAi machinery to augment and amplify the Clr4/H3K9me signal at centromeres to establish heterochromatin. Overall, our data reveal that lncRNAs and RNA quality control factors can nucleate heterochromatin and function as epigenetic silencers in eukaryotes.
DOI: 10.1016/j.cell.2024.04.042
Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00468-9