YAP drives proliferation and tumorigenesis by recruiting Mediator to super- enhancer elements (H69). Homo sapiens

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. Overall design: A total of four ChIP-Seq samples are available. Two directed against YAP using two different antibodies (Santa Cruz and Avruch), one directed against TEAD1, an unrelated IgG for background noise definition