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

Autor:	El Khattabi L; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Zhao H; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical School, Aurora CO 80045, USA., Kalchschmidt J; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Young N; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical School, Aurora CO 80045, USA., Jung S; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Van Blerkom P; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical School, Aurora CO 80045, USA., Kieffer-Kwon P; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Kieffer-Kwon KR; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Park S; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Wang X; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Krebs J; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Tripathi S; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Sakabe N; Department of Human Genetics, University of Chicago, Chicago, IL, USA., Sobreira DR; Department of Human Genetics, University of Chicago, Chicago, IL, USA., Huang SC; The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA., Rao SSP; 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., Pruett N; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Chauss D; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Sadler E; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Lopez A; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Nóbrega MA; Department of Human Genetics, University of Chicago, Chicago, IL, USA., Aiden EL; 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., Asturias FJ; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical School, Aurora CO 80045, USA. Electronic address: francisco.asturias@ucdenver.edu., Casellas R; 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.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2019 Aug 22; Vol. 178 (5), pp. 1145-1158.e20. Date of Electronic Publication: 2019 Aug 08.
DOI:	10.1016/j.cell.2019.07.011
Abstrakt:	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. (Published by Elsevier Inc.)
Databáze:	MEDLINE
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