YAP Drives Growth by Controlling Transcriptional Pause Release from Dynamic Enhancers

Giorgio G Galli, Matteo Carrara, Wei-Chien Yuan, Christian Valdes-Quezada, Basanta Gurung, Brian Pepe-Mooney, Tinghu Zhang, Geert Geeven, Nathanael S Gray, Wouter de Laat, Raffaele A Calogero, Fernando D Camargo

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

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 superenhancers with the highest transcriptional outputs. YAP modulates transcription from these elements predominantly by regulating promoter-proximal polymerase II (Pol II) 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.

Original languageEnglish
Pages (from-to)328-37
Number of pages10
JournalMolecular Cell
Volume60
Issue number2
DOIs
Publication statusPublished - 15 Oct 2015

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