YAP Drives Growth by Controlling Transcriptional Pause Release from Dynamic Enhancers
Open accessAbstract
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.
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YAP/TEAD bind distal regulatory elements to regulate transcription of target genes.
“Third, YAP/TEAD bind distal regulatory elements to regulate transcription of target genes (73-75).”
From A Tumour-Specific Molecular Network Promotes Tumour Growth in <i>Drosophila</i> by Enforcing a JNK-YKI Feedforward Loop (2023) · cites this paper as [73]
Published ChIP-seq datasets reveal a similar phenomenon in human cancer cell lines.
“Consistently, published ChIP-seq datasets34,38,39 reveal a similar phenomenon in human cancer cell lines (Figure S7F).”
From HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury (2025) · cites this paper as [34]
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- Authors
- Galli, G. G., Carrara, M., Yuan, W.-C., Valdes-Quezada, C., Gurung, B., Pepe-Mooney, B., Zhang, T., Geeven, G., Gray, N. S., de Laat, W., Calogero, R. A., & Camargo, F. D.
- Affiliations
- Boston Children's Hospital (US)
- University of Turin (IT)
- Dana-Farber Cancer Institute (US)
- University Medical Center Utrecht (NL)
- Corresponding author
- Camargo, Fernando D.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 60
- Issue
- 2
- Pages
- 328-337
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4624327
- OpenAlex
- W2121761542
- Cited by
- 290
- References
- 38
- Citations by year
- 2026: 21 · 2025: 21 · 2024: 31 · 2023: 29 · 2022: 23 · 2021: 29 · 2020: 33 · 2019: 34 · 2018: 26 · 2017: 25 · 2016: 16 · 2015: 1
- FWCI
- 12.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK099559, DK099559)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR064036, AR064036)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- YAP, Hippo signaling pathway, Mediator complex, CDK9, super-enhancers, enhancers, distal regulatory elements, transcription elongation, tissue overgrowth, carcinogenesis, chromatin occupancy
- MeSH terms
- YAP-Signaling Proteins, Transcriptional Coactivator with PDZ-Binding Motif Proteins, Animals, Antineoplastic Agents, Bile Duct Neoplasms, Chromatin, DNA Polymerase II, Enhancer Elements, Genetic, Flavonoids, Humans, Mice, Transgenic, Phosphoproteins, Piperidines, Protein Binding, Transcription Factors, Transcription, Genetic, Signal Transduction, Trans-Activators, Gene Expression Regulation, Neoplastic, Cholangiocarcinoma, Xenograft Model Antitumor Assays, Cyclin-Dependent Kinase 9, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, Mediator Complex, Carcinogenesis
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