近日，美国霍华德休斯医学院Zhe J. Liu及中国科学院深圳先进技术研究院董鹏课题组合作揭示，内聚蛋白阻止基因跨结构域共激活。该研究于2024年7月24日发表于国际一流学术期刊《自然—遗传学》杂志上。

通过分析单细胞水平上的转录组和染色质可及性，小组发现，内聚蛋白不是决定整个群体的基因表达水平，而是提供了一种广泛性功能，来中和单细胞中顺式连锁基因的随机共表达倾向。值得注意的是，在顺式中，内聚蛋白丢失会引起相隔数千万碱基的广泛基因共激活和染色质共开放。空间基因组和蛋白质成像显示，内聚蛋白阻止基因沿染色体共爆裂，并阻断转录中心的空间混合。

单分子成像显示，内聚蛋白限制了多种增强子和核心启动子结合转录调控因子的探索。总之，这些结果支持内聚蛋白安排核拓扑控制基因在单细胞中的共表达。

据介绍，内聚蛋白丢失后基因组拓扑结构的破坏，与缺乏下游基因表达变化之间的对比，引发了关于基因组和基因调控之间结构-功能关系的激烈争论。

附：英文原文

Title: Cohesin prevents cross-domain gene coactivation

Author: Dong, Peng, Zhang, Shu, Gandin, Valentina, Xie, Liangqi, Wang, Lihua, Lemire, Andrew L., Li, Wenhong, Otsuna, Hideo, Kawase, Takashi, Lander, Arthur D., Chang, Howard Y., Liu, Zhe J.

Issue&Volume: 2024-07-24

Abstract: The contrast between the disruption of genome topology after cohesin loss and the lack of downstream gene expression changes instigates intense debates regarding the structure–function relationship between genome and gene regulation. Here, by analyzing transcriptome and chromatin accessibility at the single-cell level, we discover that, instead of dictating population-wide gene expression levels, cohesin supplies a general function to neutralize stochastic coexpression tendencies of cis-linked genes in single cells. Notably, cohesin loss induces widespread gene coactivation and chromatin co-opening tens of million bases apart in cis. Spatial genome and protein imaging reveals that cohesin prevents gene co-bursting along the chromosome and blocks spatial mixing of transcriptional hubs. Single-molecule imaging shows that cohesin confines the exploration of diverse enhancer and core promoter binding transcriptional regulators. Together, these results support that cohesin arranges nuclear topology to control gene coexpression in single cells.

DOI: 10.1038/s41588-024-01852-1

Source: https://www.nature.com/articles/s41588-024-01852-1