Precise spatiotemporal gene regulation is paramount for the establishment and maintenance of cell-specific programmes. Although there is evidence that chromatin neighbourhoods, formed by the zinc-finger protein CTCF, can sequester enhancers and their target genes, there is limited in vivo evidence for CTCF demarcating super-enhancers and preventing cross talk between distinct regulatory elements. Here, we address these questions in the Wap locus with its mammary-specific super-enhancer separated by CTCF sites from widely expressed genes. Mutational analysis demonstrates that the Wap super-enhancer controls Ramp3, despite three separating CTCF sites. Their deletion in mice results in elevated expression of Ramp3 in mammary tissue through augmented promoter-enhancer interactions. Deletion of the distal CTCF-binding site results in loss of Ramp3 expression in non-mammary tissues. This suggests that CTCF sites are porous borders, allowing a super-enhancer to activate a secondary target. Likewise, CTCF sites shield a widely expressed gene from suppressive influences of a silent locus.

中文翻译：

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兼性CTCF站点适度的乳腺超增强活性，并调节非乳腺细胞中并列的基因。

精确的时空基因调控对于建立和维持特定于细胞的程序至关重要。尽管有证据表明由锌指蛋白CTCF形成的染色质邻域可以螯合增强子及其靶基因，但在体内仅有证据表明CTCF可以区分超级增强剂并防止不同调节元件之间发生串扰。在这里，我们以Wap位点来解决这些问题，其Wap位点的乳腺特异超级增强剂被CTCF位点与广泛表达的基因隔开。突变分析表明，尽管有三个单独的CTCF位点，Wap超级增强剂仍控制Ramp3。它们在小鼠中的缺失通过增强的启动子-增强子相互作用，导致Ramp3在乳腺组织中的表达升高。远端CTCF结合位点的删除导致非乳腺组织中Ramp3表达的丧失。这表明CTCF位点是多孔边界，使超级增强剂可以激活次要靶标。同样，CTCF位点保护了广泛表达的基因不受沉默基因座的抑制影响。