YAP Drives Growth by Controlling Transcriptional Pause Release from Dynamic Enhancers.
YAP Drives Growth by Controlling Transcriptional Pause Release from Dynamic Enhancers.
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YAP通过控制动态增强剂的转录暂停释放来驱动生长。
DOI：
10.1016/j.molcel.2015.09.001
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发表时间：
2015-10-15
期刊：
影响因子：
16
通讯作者：
Camargo FD
中科院分区：
文献类型：
--
作者：
Galli GG;Carrara M;Yuan WC;Valdes-Quezada C;Gurung B;Pepe-Mooney B;Zhang T;Geeven G;Gray NS;de Laat W;Calogero RA;Camargo FD
Hippo/雅普信号通路是组织生长、干细胞活性和肿瘤发生的重要调节因子。然而，雅普控制转录的机制仍有待充分阐明。在这里，我们利用全球染色质占有率分析，以证明强大的雅普结合仅限于一个相对较少的基因组中的远端调控元件。YAP占用率定义了具有最高转录输出的增强子和超级增强子的子集。雅普主要通过调节启动子近端聚合酶II（PolII）暂停释放来调节这些元件的转录。在机制上，雅普与介体复合物相互作用并将其募集到增强子，从而允许募集CDK 9延伸激酶。遗传和化学扰动实验证明，YAP驱动的过度生长和肿瘤发生表型需要介体和CDK 9。我们的研究结果揭示了雅普发挥其生长和致癌功能的分子机制，并提出了干预策略。
The Hippo/YAP signaling pathway is a crucial regulator of tissue growth, stem cell activity and tumorigenesis. However, the mechanism by which YAP controls transcription remains to be fully elucidated. Here, we utilize global chromatin occupancy analyses to demonstrate that robust YAP binding is restricted to a relatively small number of distal regulatory elements in the genome. YAP-occupancy defines a subset of enhancers and super-enhancers with the highest transcriptional outputs. YAP modulates transcription from these elements predominantly by regulating promoter-proximal Polymerase II (PolII) pause release. Mechanistically, YAP interacts and recruits the Mediator complex to enhancers, allowing the recruitment of the CDK9 elongating kinase. Genetic and chemical perturbation experiments demonstrate the requirement for Mediator and CDK9 in YAP-driven phenotypes of overgrowth and tumorigenesis. Our results here uncover the molecular mechanisms employed by YAP to exert its growth and oncogenic functions, and suggest strategies for intervention.