中国科学院广州生物医药与健康研究院何俊等研究人员合作，揭示了Rpd3S组蛋白去乙酰化酶复合物进行核小体去乙酰化和DNA连接紧密化的结构基础。相关论文于2023年9月4日在线发表在《细胞研究》杂志上。

研究人员表示，在酿酒酵母（Saccharomyces cerevisiae）中，Sin3组蛋白去乙酰化酶（HDAC）复合物Rpd3S的活性阻止了编码区的隐蔽转录，该复合物由转录RNA聚合酶II（RNAPII）携带，用于去乙酰化和稳定染色质。尽管Rpd3S具有重要的基础作用，但其去乙酰化核小体和调节染色质动态的机制仍然难以捉摸。

研究人员测定了Rpd3S与核小体核心颗粒（NCP）复合物的几种冷冻电镜结构，包括H3/H4去乙酰化状态、可变去乙酰化状态、连接体收紧状态以及Rpd3S与NCP上Hho1连接组蛋白共存的状态。这些结构表明，Rpd3S利用保守的Sin3基本表面在核小体DNA中导航，通过与H3K36甲基化和核糖体DNA外连接体的相互作用，以乙酰化的H3K9为靶标，并对其他组蛋白尾部进行取样。此外，这些结构还表明，Rpd3S会重新配置DNA连接体，并与 Hho1协同作用来参与NCP，从而有可能揭示Rpd3S和Hho1如何协同作用以实现基因沉默。

附：英文原文

Title: Structural basis of nucleosome deacetylation and DNA linker tightening by Rpd3S histone deacetylase complex

Author: Dong, Shuqi, Li, Huadong, Wang, Meilin, Rasheed, Nadia, Zou, Binqian, Gao, Xijie, Guan, Jiali, Li, Weijie, Zhang, Jiale, Wang, Chi, Zhou, Ningkun, Shi, Xue, Li, Mei, Zhou, Min, Huang, Junfeng, Li, He, Zhang, Ying, Wong, Koon Ho, Zhang, Xiaofei, Chao, William Chong Hang, He, Jun

Issue&Volume: 2023-09-04

Abstract: In Saccharomyces cerevisiae, cryptic transcription at the coding region is prevented by the activity of Sin3 histone deacetylase (HDAC) complex Rpd3S, which is carried by the transcribing RNA polymerase II (RNAPII) to deacetylate and stabilize chromatin. Despite its fundamental importance, the mechanisms by which Rpd3S deacetylates nucleosomes and regulates chromatin dynamics remain elusive. Here, we determined several cryo-EM structures of Rpd3S in complex with nucleosome core particles (NCPs), including the H3/H4 deacetylation states, the alternative deacetylation state, the linker tightening state, and a state in which Rpd3S co-exists with the Hho1 linker histone on NCP. These structures suggest that Rpd3S utilizes a conserved Sin3 basic surface to navigate through the nucleosomal DNA, guided by its interactions with H3K36 methylation and the extra-nucleosomal DNA linkers, to target acetylated H3K9 and sample other histone tails. Furthermore, our structures illustrate that Rpd3S reconfigures the DNA linkers and acts in concert with Hho1 to engage the NCP, potentially unraveling how Rpd3S and Hho1 work in tandem for gene silencing.

DOI: 10.1038/s41422-023-00869-1

Source: https://www.nature.com/articles/s41422-023-00869-1