title: YAP Drives Growth by Controlling Transcriptional Pause Release from Dynamic Enhancers.
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.
authors.affiliation: Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA.
authors.forename: Giorgio G
authors.initials: GG
authors.lastname: Galli
authors.affiliation: Molecular Biotechnology Center, Department of Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Carrara
authors.affiliation: Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA.
authors.forename: Wei-Chien
authors.initials: WC
authors.lastname: Yuan
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, the Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Valdes-Quezada
authors.affiliation: Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA.
authors.forename: Basanta
authors.initials: B
authors.lastname: Gurung
authors.affiliation: Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Pepe-Mooney
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Tinghu
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, the Netherlands.
authors.forename: Geert
authors.initials: G
authors.lastname: Geeven
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, the Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: de Laat
authors.affiliation: Molecular Biotechnology Center, Department of Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
authors.forename: Raffaele A
authors.initials: RA
authors.lastname: Calogero
authors.affiliation: Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA. Electronic address: camargo@fas.harvard.edu.
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Camargo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics / Q000378:metabolism; D004257:DNA Polymerase II / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D056892:Mediator Complex / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011485:Protein Binding; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors; D014158:Transcription, Genetic; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D023041:Xenograft Model Antitumor Assays; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002843:Chromatin; D005419:Flavonoids; D047908:Intracellular Signaling Peptides and Proteins; D056892:Mediator Complex; D010750:Phosphoproteins; D010880:Piperidines; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; C517794:Wwtr1 protein, mouse; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C077990:alvocidib; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9; D004257:DNA Polymerase II