YAP drives growth by controlling transcriptional pause release from dynamic enhancers (HuCCT1)

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 tumorigenesisHowever, 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.