Cited by 253Genomics and Chromatin DynamicsChromatin Remodeling and CancerNuclear Structure and Function

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A Pliable Mediator Acts as a Functional Rather Than an Architectural Bridge between Promoters and Enhancers

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El Khattabi, Laila, Zhao, Haiyan, Kalchschmidt, Jens, Young, Natalie, Jung, Seolkyoung, Van Blerkom, Peter, Kieffer-Kwon, Philippe, Kieffer-Kwon, Kyong-Rim, Park, Solji, Wang, Xiang, Krebs, Jordan, Tripathi, Subhash, Sakabe, Noboru, Sobreira, Débora R., Huang, Su-Chen, Rao, Suhas S.P., Pruett, Nathanael, Chauss, Daniel, Sadler, Erica, Lopez, Andrea, Nóbrega, Marcelo A., Aiden, Erez Lieberman, Asturias, Francisco J., Casellas, Rafael·2019·Cell

DOI 10.1016/j.cell.2019.07.011PMC PMC7533040

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Abstract

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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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: Zhao, Haiyan
Kalchschmidt, Jens
Young, Natalie
Jung, Seolkyoung
Wang, Xiang
Tripathi, Subhash
Sakabe, Noboru
Sobreira, Débora R.
Rao, Suhas S.P.
Pruett, Nathanael
Chauss, Daniel
Sadler, Erica
Lopez, Andrea
Nóbrega, Marcelo A.
Aiden, Erez Lieberman
Asturias, Francisco J.
Casellas, Rafael
Venue: Cell
Publisher: Elsevier BV
Published: 2019-08
Volume: 178
Issue: 5
Pages: 1145-1158.e20
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2019.07.011
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 387 d)
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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A Pliable Mediator Acts as a Functional Rather Than an Architectural Bridge between Promoters and Enhancers

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