小柯机器人

清华大学李海涛等研究人员合作揭示Rpd3S在H3K36me3引导下进行核小体去乙酰化的多种模式。2023年7月19日，《自然》杂志在线发表了这项成果。

据研究人员介绍，与上下文相关的动态组蛋白修饰是基因调控的一个关键表观遗传机制。Rpd3小复合物（Rpd3S）能识别组蛋白H3在第36位赖氨酸上的三甲基化（H3K36me3），并在转录区域的多个位点对组蛋白H3和H4进行去乙酰化。

研究人员解析了酿酒酵母Rpd3S在游离态和H3K36me3核小体结合态下的冷冻电镜结构。研究人员展示了Rpd3S的独特结构，其中两份Eaf3-Rco1异源二聚体与Rpd3和Sin3不对称地组装在一起，形成一个催化核心复合物。Eaf3、Sin3和Rco1可多价识别两个H3K36me3标记、核小体DNA和连接DNA，从而将Rpd3的催化中心定位在组蛋白H4 N 端尾部的旁边，进行去乙酰化。在另一种催化模式中，Rco1和Eaf3对未甲基化的组蛋白H3第四位赖氨酸和H3K36me3进行组合读取，引导组蛋白H3特异性去乙酰化，但组蛋白H3乙酰化的第9位赖氨酸除外。

总之，这项工作说明了Rpd3S多价核小体参与和甲基化引导的去乙酰化的动态和多样化模式，并凸显了在转录及其他过程中通过精心设计的多亚基酶机制进行表观遗传调控的精致复杂性。

附：英文原文

Title: Diverse modes of H3K36me3-guided nucleosomal deacetylation by Rpd3S

Author: Guan, Haipeng, Wang, Pei, Zhang, Pei, Ruan, Chun, Ou, Yutian, Peng, Bo, Zheng, Xiangdong, Lei, Jianlin, Li, Bing, Yan, Chuangye, Li, Haitao

Issue&Volume: 2023-07-19

Abstract: Context-dependent dynamic histone modifications constitute a key epigenetic mechanism in gene regulation1,2,3,4. The Rpd3 small (Rpd3S) complex recognizes histone H3 trimethylation on lysine 36 (H3K36me3) and deacetylates histones H3 and H4 at multiple sites across transcribed regions5,6,7. Here we solved the cryo-electron microscopy structures of Saccharomyces cerevisiae Rpd3S in its free and H3K36me3 nucleosome-bound states. We demonstrated a unique architecture of Rpd3S, in which two copies of Eaf3–Rco1 heterodimers are asymmetrically assembled with Rpd3 and Sin3 to form a catalytic core complex. Multivalent recognition of two H3K36me3 marks, nucleosomal DNA and linker DNAs by Eaf3, Sin3 and Rco1 positions the catalytic centre of Rpd3 next to the histone H4 N-terminal tail for deacetylation. In an alternative catalytic mode, combinatorial readout of unmethylated histone H3 lysine 4 and H3K36me3 by Rco1 and Eaf3 directs histone H3-specific deacetylation except for the registered histone H3 acetylated lysine 9. Collectively, our work illustrates dynamic and diverse modes of multivalent nucleosomal engagement and methylation-guided deacetylation by Rpd3S, highlighting the exquisite complexity of epigenetic regulation with delicately designed multi-subunit enzymatic machineries in transcription and beyond.

DOI: 10.1038/s41586-023-06349-1

Source: https://www.nature.com/articles/s41586-023-06349-1

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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