Otto-Warburg-Laboratory, Max Planck Institute for Molecular Genetics, 14195, Berlin, Germany.
Department of Mathematics and Computer Science, Freie Universität Berlin, 14195, Berlin, Germany.
Nat Commun. 2023 Aug 17;14(1):4971. doi: 10.1038/s41467-023-40633-y.
Gene transcription by RNA polymerase II (Pol II) is under control of promoters and distal regulatory elements known as enhancers. Enhancers are themselves transcribed by Pol II correlating with their activity. How enhancer transcription is regulated and coordinated with transcription at target genes has remained unclear. Here, we developed a high-sensitive native elongating transcript sequencing approach, called HiS-NET-seq, to provide an extended high-resolution view on transcription, especially at lowly transcribed regions such as enhancers. HiS-NET-seq uncovers new transcribed enhancers in human cells. A multi-omics analysis shows that genome-wide enhancer transcription depends on the BET family protein BRD4. Specifically, BRD4 co-localizes to enhancer and promoter-proximal gene regions, and is required for elongation activation at enhancers and their genes. BRD4 keeps a set of enhancers and genes in proximity through long-range contacts. From these studies BRD4 emerges as a general regulator of enhancer transcription that may link transcription at enhancers and genes.
RNA 聚合酶 II（Pol II）介导的基因转录受到启动子和远端调控元件（如增强子）的控制。增强子本身也被 Pol II 转录，与其活性相关。然而，增强子转录是如何被调控的，以及如何与靶基因的转录相协调，仍然不清楚。在这里，我们开发了一种高灵敏度的天然延伸转录测序方法，称为 HiS-NET-seq，以提供对转录的扩展的高分辨率视图，特别是在低转录区域，如增强子。HiS-NET-seq 在人类细胞中发现了新的转录增强子。多组学分析表明，全基因组范围的增强子转录依赖于 BET 家族蛋白 BRD4。具体来说，BRD4 与增强子和启动子近端基因区域共定位，并在增强子及其基因的延伸激活中是必需的。BRD4 通过长距离接触将一组增强子和基因保持在接近的位置。从这些研究中，BRD4 作为增强子转录的通用调节剂出现，它可能连接增强子和基因的转录。
