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.

粘连蛋白丢失后基因组拓扑结构的破坏与下游基因表达变化缺乏之间的对比引发了关于基因组和基因调控之间的结构-功能关系的激烈争论。在这里，通过分析单细胞水平的转录组和染色质可及性，我们发现，粘连蛋白不是决定群体范围的基因表达水平，而是提供了中和单细胞中顺式连接基因的随机共表达倾向的一般功能。值得注意的是，粘连蛋白损失会诱导广泛的基因共激活和染色质共开放，顺式中相距数千万个碱基。空间基因组和蛋白质成像表明，粘连蛋白可防止基因沿染色体共爆发，并阻止转录中心的空间混合。单分子成像表明，粘连蛋白限制了对多种增强子和核心启动子结合转录调节因子的探索。总之，这些结果支持粘连蛋白排列核拓扑来控制单细胞中的基因共表达。