YAP drives proliferation and tumorigenesis by recruiting Mediator to super- enhancer elements (CClp1)

The Hippo/YAP signaling pathway is a crucial regulator of tissue growth and stem cell activity. YAP is also a powerful driver of tumor growth and its nuclear accumulation is frequently observed in human cancer. However, the molecular mechanism employed by YAP to orchestrate transcriptional outputs are undefined. Here, we utilize genomic technologies to demonstrate that YAP occupancy is restricted to a small number of distal regulatory elements highly enriched for superenhancers. Target genes associated with these elements are selectively sensitive to the loss of YAP in cancer cells. YAP directs recruitment of the Mediator complex to activate transcriptional regulation from these enhancers without affecting chromatin organization We also provide in vivo genetic evidence that loss of Mediator rescues YAP-driven cancer cell proliferation and organ overgrowth. Our data provide a molecular mechanism behind YAP-driven tumorigenesis, and highlights transcriptional control as a potential therapeutic strategy for YAP-driven cancers. A total of eight ChIP-Seq samples are available. Three directed against YAP using two different antibodies (Santa Cruz, Avruch and a replicate of the Avruch run), one directed against a tagged version of YAP (C25) and its own specific control (BirA), one directed against TEAD1, the whole genomic input DNA, an unrelated IgG for background noise definition

Hippo/YAP信号通路是调控组织生长与干细胞活性的关键通路。YAP同时也是强效的肿瘤生长驱动因子，其核蓄积现象在人类癌症中十分常见。然而，YAP协调转录输出的分子机制迄今尚未明确。本研究借助基因组学技术证实，YAP的结合位点仅局限于少量远端调控元件，且这些元件极显著富集于超级增强子区域。与这些元件关联的靶基因，在癌细胞中对YAP的缺失呈现出高度选择性敏感。YAP可介导中介体复合物（Mediator complex）的招募，以激活这些增强子的转录调控程序，且不会对染色质组织结构造成影响。我们还通过体内遗传学实验提供了确凿证据，证实中介体复合物的缺失能够挽救YAP驱动的癌细胞增殖与器官过度生长表型。本研究数据阐明了YAP驱动肿瘤发生的分子机制，并凸显出转录调控可作为YAP驱动型癌症的潜在治疗策略。本次研究共包含8个ChIP-Seq（染色质免疫共沉淀测序）样本：其中3个针对YAP蛋白，使用两种不同抗体（Santa Cruz、Avruch，以及Avruch抗体实验的重复样本）；1个针对带有标签的YAP变体（C25）及其专属对照样本（BirA）；1个针对TEAD1蛋白；1个为全基因组输入DNA样本；以及1个用于界定本底噪声的无关IgG（免疫球蛋白G）抗体样本。