National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20892, USA.
Nucleic Acids Res. 2021 May 7;49(8):4493-4505. doi: 10.1093/nar/gkab235.
An essential questions of gene regulation is how large number of enhancers and promoters organize into gene regulatory loops. Using transcription-factor binding enrichment as an indicator of enhancer strength, we identified a portion of H3K27ac peaks as potentially strong enhancers and found a universal pattern of promoter and enhancer distribution: At actively transcribed regions of length of ∼200-300 kb, the numbers of active promoters and enhancers are inversely related. Enhancer clusters are associated with isolated active promoters, regardless of the gene's cell-type specificity. As the number of nearby active promoters increases, the number of enhancers decreases. At regions where multiple active genes are closely located, there are few distant enhancers. With Hi-C analysis, we demonstrate that the interactions among the regulatory elements (active promoters and enhancers) occur predominantly in clusters and multiway among linearly close elements and the distance between adjacent elements shows a preference of ∼30 kb. We propose a simple rule of spatial organization of active promoters and enhancers: Gene transcriptions and regulations mainly occur at local active transcription hubs contributed dynamically by multiple elements from linearly close enhancers and/or active promoters. The hub model can be represented with a flower-shaped structure and implies an enhancer-like role of active promoters.
基因调控的一个基本问题是，大量的增强子和启动子如何组织成基因调控回路。我们使用转录因子结合富集作为增强子强度的指标，确定了一部分 H3K27ac 峰作为潜在的强增强子，并发现了启动子和增强子分布的普遍模式：在长度约为 200-300kb 的活跃转录区域，活跃启动子和增强子的数量呈反比关系。增强子簇与孤立的活跃启动子相关，而与基因的细胞类型特异性无关。随着附近活跃启动子数量的增加，增强子的数量减少。在多个活跃基因紧密排列的区域，很少有遥远的增强子。通过 Hi-C 分析，我们证明了调控元件（活跃的启动子和增强子）之间的相互作用主要发生在簇中，以及线性接近元件之间的多方式相互作用，并且相邻元件之间的距离表现出约 30kb 的偏好。我们提出了一个活跃的启动子和增强子的空间组织的简单规则：基因转录和调控主要发生在由线性接近的增强子和/或活跃启动子的多个元件动态贡献的局部活跃转录中心。该中心模型可以用花形结构来表示，并暗示了活跃启动子的增强子样作用。
