Several studies have now described instances where G-rich sequences in promoters and enhancers regulate gene expression through forming G-quadruplex (G4) structures. Relatedly, our group recently identified 301 long genomic stretches significantly enriched for minimal G4 motifs (LG4s) in humans and found the majority of these overlap annotated enhancers, and furthermore, that the promoters regulated by these LG4 enhancers are similarly enriched with G4-capable sequences. While the generally accepted model for enhancer:promoter specificity maintains that interactions are dictated by enhancer- and promoter-bound transcriptional activator proteins, the current study tested an alternative hypothesis: that LG4 enhancers interact with cognate promoters via a direct G4:G4 DNA-based mechanism. This work establishes the nuclear proximity of LG4 enhancer:promoter pairs, biochemically demonstrates the ability of individual LG4 single-stranded DNAs (ssDNAs) to directly interact target promoter ssDNAs, and confirms that these interactions, as well as the ability of LG4 enhancers to activate target promoters in culture, are mediated by G4 DNA.

中文翻译：

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富含 G4 的长增强子通过基于 G4 DNA 的机制靶向启动子


现在有几项研究描述了启动子和增强子中富含 G 的序列通过形成 G 四链体 （G4） 结构来调节基因表达的情况。与此相关，我们小组最近在人类中发现了 301 个长基因组片段，这些片段显著富集了人类的最小 G4 基序 （LG4），并发现其中大多数重叠注释的增强子，此外，受这些 LG4 增强子调节的启动子同样富含 G4 能力序列。虽然普遍接受的增强子：启动子特异性模型坚持认为相互作用是由增强子和启动子结合的转录激活子蛋白决定的，但目前的研究测试了另一种假设：LG4 增强子通过基于 G4：G4 DNA 的直接机制与同源启动子相互作用。这项工作建立了 LG4 增强子：启动子对的核接近性，生化证明了单个 LG4 单链 DNA （ssDNA） 直接相互作用靶启动子 ssDNA 的能力，并证实这些相互作用以及 LG4 增强子在培养物中激活靶启动子的能力是由 G4 DNA 介导的。