GSE68170
YAP drives growth by controlling transcriptional pause release from dynamic enhancers (MSTO)
The Hippo/YAP signaling pathway is a crucial regulator of tissue growth and stem cell activity.YAP, a transcriptional co-activator and main effector of the pathway,   is   also   a   powerful   driver   of   tumorigenesis However, the genetic program regulated by YAP and 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. We  find  that  YAP  modulates  transcription  from  these elements  predominantly  by regulating  promoter-proximal  Polymerase  II  (PolII) pause  release. Mechanistically, YAP physically interacts and recruits the Mediator complex to enhancers, which then allows for 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 new strategies for intervention. Overall design: A total of four ChIP-Seq samples are available. One directed against YAP, one directed against TEAD1, one directed against the histone mark H3K27ac and an unrelated IgG for background noise definition