Ren Gang, Jin Wenfei, Cui Kairong, Rodrigez Joseph, Hu Gangqing, Zhang Zhiying, Larson Daniel R, Zhao Keji
Systems Biology Center, Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China.
Systems Biology Center, Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Mol Cell. 2017 Sep 21;67(6):1049-1058.e6. doi: 10.1016/j.molcel.2017.08.026.
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方面也存在异质性。尽管启动子结构对细菌和低等真核生物中基因表达的细胞间差异有至关重要的影响，但哺乳动物中是什么控制基因表达噪声仍不清楚。在此我们报告，CTCF通过稳定增强子与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结构域（TADs）内的增强子相互交织，并且在CTCF结合与相关增强子的活性之间发现了正相关。CTCF位点的缺失会损害增强子与启动子的相互作用。使用单细胞流式细胞术和单分子RNA-FISH分析，我们证明敲低CTCF或删除CTCF结合位点会导致基因表达的细胞间差异增加，这表明由CTCF介导的远距离启动子-增强子相互作用在控制哺乳动物细胞中基因表达的细胞间差异方面发挥重要作用。
