2. Academic Validation
  3. A Pliable Mediator Acts as a Functional Rather Than an Architectural Bridge between Promoters and Enhancers

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

  • Cell. 2019 Aug 22;178(5):1145-1158.e20. doi: 10.1016/j.cell.2019.07.011.
Laila El Khattabi 1,  Haiyan Zhao 2,  Jens Kalchschmidt 1,  Natalie Young 2,  Seolkyoung Jung 1,  Peter Van Blerkom 2,  Philippe Kieffer-Kwon 1,  Kyong-Rim Kieffer-Kwon 1,  Solji Park 1,  Xiang Wang 1,  Jordan Krebs 1,  Subhash Tripathi 1,  Noboru Sakabe 3,  Débora R Sobreira 3,  Su-Chen Huang 4,  Suhas S P Rao 5,  Nathanael Pruett 1,  Daniel Chauss 1,  Erica Sadler 1,  Andrea Lopez 1,  Marcelo A Nóbrega 3,  Erez Lieberman Aiden 6,  Francisco J Asturias 7,  Rafael Casellas 8
Affiliations

Affiliations

  • 1 Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA.
  • 2 Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical School, Aurora CO 80045, USA.
  • 3 Department of Human Genetics, University of Chicago, Chicago, IL, USA.
  • 4 The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA.
  • 5 The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 6 The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China.
  • 7 Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical School, Aurora CO 80045, USA. Electronic address: francisco.asturias@ucdenver.edu.
  • 8 Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA; Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA. Electronic address: rafael.casellas@nih.gov.
PMID: 31402173 DOI: 10.1016/j.cell.2019.07.011
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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