中国科学院生物物理研究所朱平等研究人员合作揭示链接组蛋白H5与核小体结合及染色质纤维压缩的结构基础。2024年8月5日，国际知名学术期刊《细胞研究》在线发表了这一成果。

研究人员报告了以3.6埃分辨率的冷冻电子显微镜技术解析的H5结合的十二核小体结构，即在链接组蛋白H5存在下重构的染色质纤维。该结构展示了一个由四聚核小体单元扭曲的双螺旋左手结构。研究人员建立了H5结合染色质纤维的原子结构模型，包括一个完整的染色质体，提供了H5组蛋白全长的结构细节，涵盖了其N端结构域和类似HMG基序的C端结构域。染色质体结构显示，H5通过三种接触模式结合核小体，并且H5在染色质纤维中的结合位置位于核小体的偏心位置。

更重要的是，H5-染色质结构提供了精细的分子基础，用于解析四聚核小体单元内和四聚核小体单元间的相互作用。此外，研究人员通过一系列酵母遗传和基因组学研究以及体外生物物理实验系统地验证了四聚核小体单元的生理功能和结构特征。进一步地，这些结构揭示了组蛋白尾部的多个结构不对称性赋予了染色质纤维极性。这些发现提供了关于核小体阵列如何折叠成具有极性的更高阶染色质纤维的结构和机制的深刻见解，并涵盖了体内外的情况。

据介绍，染色质纤维的层级包装在基因调控中发挥着至关重要的作用。30纳米染色质纤维作为连接核小体阵列与更高阶结构的中心结构，功能上作为转录沉默染色质的第一层级。30纳米染色质纤维的动态变化对与DNA相关的生物过程至关重要。

附：英文原文

Title: Structural basis for linker histone H5–nucleosome binding and chromatin fiber compaction

Author: Li, Wenyan, Hu, Jie, Song, Feng, Yu, Juan, Peng, Xin, Zhang, Shuming, Wang, Lin, Hu, Mingli, Liu, Jia-Cheng, Wei, Yu, Xiao, Xue, Li, Yan, Li, Dongyu, Wang, Hui, Zhou, Bing-Rui, Dai, Linchang, Mou, Zongjun, Zhou, Min, Zhang, Haonan, Zhou, Zheng, Zhang, Huidong, Bai, Yawen, Zhou, Jin-Qiu, Li, Wei, Li, Guohong, Zhu, Ping

Issue&Volume: 2024-08-05

Abstract: The hierarchical packaging of chromatin fibers plays a critical role in gene regulation. The 30-nm chromatin fibers, a central-level structure bridging nucleosomal arrays to higher-order organizations, function as the first level of transcriptional dormant chromatin. The dynamics of 30-nm chromatin fiber play a crucial role in biological processes related to DNA. Here, we report a 3.6-angstrom resolution cryogenic electron microscopy structure of H5-bound dodecanucleosome, i.e., the chromatin fiber reconstituted in the presence of linker histone H5, which shows a two-start left-handed double helical structure twisted by tetranucleosomal units. An atomic structural model of the H5-bound chromatin fiber, including an intact chromatosome, is built, which provides structural details of the full-length linker histone H5, including its N-terminal domain and an HMG-motif-like C-terminal domain. The chromatosome structure shows that H5 binds the nucleosome off-dyad through a three-contact mode in the chromatin fiber. More importantly, the H5-chromatin structure provides a fine molecular basis for the intra-tetranucleosomal and inter-tetranucleosomal interactions. In addition, we systematically validated the physiological functions and structural characteristics of the tetranucleosomal unit through a series of genetic and genomic studies in Saccharomyces cerevisiae and in vitro biophysical experiments. Furthermore, our structure reveals that multiple structural asymmetries of histone tails confer a polarity to the chromatin fiber. These findings provide structural and mechanistic insights into how a nucleosomal array folds into a higher-order chromatin fiber with a polarity in vitro and in vivo.

DOI: 10.1038/s41422-024-01009-z

Source: https://www.nature.com/articles/s41422-024-01009-z