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

L. El Khattabi, Haiyan Zhao, Jens Kalchschmidt, Natalie Young, Seolkyoung Jung, P. Van Blerkom, Philippe Kieffer-Kwon, Kyong Rim Kieffer-Kwon, S. Park, X. Wang, Jordan Krebs, Subhash Tripathi, Noboru Sakabe, Débora R. Sobreira, Su Chen Huang, Suhas S.P. Rao, Nathanael Pruett, Daniel Chauss, E. Sadler, Andrea LopezMarcelo A. Nóbrega, Erez Lieberman Aiden, Francisco J. Asturias, Rafael Casellas

Research output: Contribution to journalArticlepeer-review

138 Citations (Scopus)


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. A structurally-conserved Mediator promotes and controls interactions between enhancers and promoters but is not itself necessary to tether these elements.

Original languageEnglish
Pages (from-to)1145-1158.e20
Issue number5
Publication statusPublished - 22 Aug 2019
Externally publishedYes


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