TY - JOUR
T1 - YAP Drives Growth by Controlling Transcriptional Pause Release from Dynamic Enhancers
AU - Galli, Giorgio G.
AU - Carrara, Matteo
AU - Yuan, Wei Chien
AU - Valdes-Quezada, Christian
AU - Gurung, Basanta
AU - Pepe-Mooney, Brian
AU - Zhang, Tinghu
AU - Geeven, Geert
AU - Gray, Nathanael S.
AU - de Laat, Wouter
AU - Calogero, Raffaele A.
AU - Camargo, Fernando D.
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/10/15
Y1 - 2015/10/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84944897345&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2015.09.001
DO - 10.1016/j.molcel.2015.09.001
M3 - Article
C2 - 26439301
AN - SCOPUS:84944897345
SN - 1097-2765
VL - 60
SP - 328
EP - 337
JO - Molecular Cell
JF - Molecular Cell
IS - 2
ER -