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A Pliable Mediator Acts as a Functional Rather Than an Architectural Bridge between Promoters and Enhancers
Open accessAbstract
While Mediator plays a key role in eukaryotic transcription, little is known about its mechanism of action. This study combines CRISPR-Cas9 genetic screens, degron assays, Hi-C, and cryoelectron microscopy (cryo-EM) to dissect the function and structure of mammalian Mediator (mMED). Deletion analyses in B, T, and embryonic stem cells (ESC) identified a core of essential subunits required for Pol II recruitment genome-wide. Conversely, loss of non-essential subunits mostly affects promoters linked to multiple enhancers. Contrary to current models, however, mMED and Pol II are dispensable to physically tether regulatory DNA, a topological activity requiring architectural proteins. Cryo-EM analysis revealed a conserved core, with non-essential subunits increasing structural complexity of the tail module, a primary transcription factor target. Changes in tail structure markedly increase Pol II and kinase module interactions. We propose that Mediator's structural pliability enables it to integrate and transmit regulatory signals and act as a functional, rather than an architectural bridge, between promoters and enhancers.
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“However, Promoter Capture Hi-C-based studies did not observe a significant change in enhancer–promoter contacts upon RNAP inhibition, including in cells rapidly depleted of cohesin or CTCF [349, 380].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [380]
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“However, it was shown recently that rapid removal of chromatin-bound Mediator and RNAP does not significantly affect chromosomal architecture, including enhancer–promoter interactions, in spite of triggering widespread transcriptional changes and cell cycle arrest [380].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [380]
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Metadata
- Authors
- El Khattabi, L., Zhao, H., Kalchschmidt, J., Young, N., Jung, S., Van Blerkom, P., Kieffer-Kwon, P., Kieffer-Kwon, K.-R., Park, S., Wang, X., Krebs, J., Tripathi, S., Sakabe, N., Sobreira, D. R., Huang, S.-C., Rao, S. S. P., Pruett, N., Chauss, D., Sadler, E., Lopez, A., Nóbrega, M. A., Aiden, E. L., Asturias, F. J., & Casellas, R.
- Affiliations
- University of Colorado Anschutz (US)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (US)
- University of Chicago (US)
- Baylor College of Medicine (US)
- National Institutes of Health (US)
- Corresponding author
- Asturias, Francisco J.
- Casellas, Rafael
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 178
- Issue
- 5
- Pages
- 1145-1158.e20
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7533040
- OpenAlex
- W2967977322
- Cited by
- 244
- References
- 102
- Citations by year
- 2026: 26 · 2025: 22 · 2024: 38 · 2023: 35 · 2022: 44 · 2021: 51 · 2020: 25 · 2019: 3
- FWCI
- 10.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- Mediator complex, RNA polymerase II recruitment, enhancers, transcriptional regulation, Hi-C, cryo-electron microscopy
- MeSH terms
- Mouse Embryonic Stem Cells, Gene Editing, Cohesins, Animals, Cells, Cultured, Chromosomal Proteins, Non-Histone, Enhancer Elements, Genetic, Humans, Male, Mice, Inbred C57BL, Promoter Regions, Genetic, RNA Polymerase II, Saccharomyces cerevisiae, CD4-Positive T-Lymphocytes, Cell Cycle Proteins, Cryoelectron Microscopy, Protein Structure, Quaternary, Saccharomyces cerevisiae Proteins, Mice, Mediator Complex, CRISPR-Cas Systems
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