The bromodomain and extraterminal domain (BET) family of proteins are critical chromatin readers that bind to acetylated histones through their bromodomains to activate transcription. Here, we reveal that bromodomain inhibition fails to repress oncogenic targets of estrogen receptor because of an intrinsic transcriptional mechanism. While bromodomains are necessary for the transcription of many genes, bromodomain-containing protein 4 (BRD4) binds to estrogen receptor binding sites and activates transcription of critical oncogenes such as MYC, independently of its bromodomains. BRD4 associates with the Mediator complex and disruption of Mediator reduces BRD4’s enhancer occupancy. Profiling changes of the post-initiation RNA polymerase II (Pol II)-associated factors revealed that BET proteins regulate interactions between Pol II and elongation factors SPT5, SPT6 and the polymerase-associated factor 1 complex, which associate with BET proteins independently of their bromodomains and mediate their transcription elongation effect. Our findings highlight the importance of bromodomain-independent functions and interactions of BET proteins in the development of future therapeutic strategies.

溴结构域和末端外结构域 （BET） 蛋白家族是关键的染色质读取器，通过其溴结构域与乙酰化组蛋白结合以激活转录。在这里，我们揭示了由于内在的转录机制，溴结构域抑制无法抑制雌激素受体的致癌靶标。虽然溴结构域是许多基因转录所必需的，但含溴结构域的蛋白 4 （BRD4） 与雌激素受体结合位点结合并激活关键癌基因（如 MYC）的转录，独立于其溴结构域。BRD4 与 Mediator 复合体结合，Mediator 的破坏降低了 BRD4 的增强子占有率。分析起始后 RNA 聚合酶 II （Pol II） 相关因子的变化表明，BET 蛋白调节 Pol II 与延伸因子 SPT5、SPT6 和聚合酶相关因子 1 复合物之间的相互作用，这些复合物独立于其溴结构域与 BET 蛋白结合并介导其转录延伸效应。我们的研究结果强调了 BET 蛋白的溴结构域非依赖性功能和相互作用在未来治疗策略开发中的重要性。