Recent studies indicate that even a homogeneous population of cells display heterogeneity in gene expression and response to environmental stimuli. Although promoter structure critically influences the cell-to-cell variation of gene expression in bacteria and lower eukaryotes, it remains unclear what controls the gene expression noise in mammals. Here we report that CTCF decreases cell-to-cell variation of expression by stabilizing enhancer-promoter interaction. We show that CTCF binding sites are interwoven with enhancers within topologically associated domains (TADs) and a positive correlation is found between CTCF binding and the activity of the associated enhancers. Deletion of CTCF sites compromises enhancer-promoter interactions. Using single-cell flow cytometry and single-molecule RNA-FISH assays, we demonstrate that knocking down of CTCF or deletion of a CTCF binding site results in increased cell-to-cell variation of gene expression, indicating that long-range promoter-enhancer interaction mediated by CTCF plays important roles in controlling the cell-to-cell variation of gene expression in mammalian cells.

最近的研究表明，即使是同质的细胞群体，在基因表达和对环境刺激的反应中也表现出异质性。尽管启动子结构严重影响细菌和低等真核生物中基因表达的细胞间变化，但仍不清楚是什么控制哺乳动物中基因表达的噪音。在这里，我们报道CTCF通过稳定增强子-启动子的相互作用来降低表达的细胞间差异。我们表明，CTCF结合位点与拓扑相关域（TADs）中的增强子交织在一起，并且在CTCF结合与相关增强子的活性之间发现正相关。CTCF位点的缺失损害了增强子-启动子的相互作用。使用单细胞流式细胞仪和单分子RNA-FISH分析，