The Mediator of transcriptional regulation was first characterized in yeast and is the central coactivator that enables a response of RNA polymerase II (Pol II) to activators and repressors (Kelleher et al., 1990, Richter et al., 2020). As a multi-protein complex, Mediator connects DNA-binding TFs with RNA polymerase II (Pol II) and thus serves as a central hub to regulate diverse aspects of transcription. The overall structure of the Mediator complex involves three major modules (Head, Middle, and Tail). The head and middle modules interact with Pol II, while the tail module interacts with various transcription factors (Khan et al., 2022, Malik et al., 2020). The middle module includes MED1, MED4, MED7, MED9, MED10, MED19, MED21, MED26 and MED31 (Koschubs et al., 2010, Richter et al., 2020). The mediator complex also associates transiently with a CDK8 kinase module (Hasan et al., 2020). The CDK8 module is conserved in all eukaryotes and consists of 4 proteins: CDK8, CYCLIN C (CYCC), MED12, and MED13 (Alonso-Nieves et al., 2021).

MED7 is a component of the middle module of Mediator, and has been shown to serve as a binding platform, with its C-terminus associated with MED21, and its N-terminus associated with MED31. The middle module subunits MED1 and MED10, which bridge to the Mediator tail module, also bind MED7 (Koschubs et al., 2010).

Crystal structure analysis of the MED7/MED21 heterodimer showed a four helix bundle domain, and a coiled-coil protrusion connected by a flexible hinge. Four putative protein binding sites allow for assembly of the middle module and binding of MED6, which bridges to the Mediator head module. This flexible bridge could account for changes in Mediator conformation upon binding to RNA pol II or activators/repressors. (Baumli et al., 2005, Maji et al., 2019). The N-terminal MED7/MED31 submodule shows a conserved novel fold, two proline-rich stretches in the N-terminus of MED7 wrapping around the right-handed four-helix bundle of Med31 (Koschubs et al., 2009, Chen et al., 2021).

AtMED7 is encoded by two paralogs in Arabidopsis and Maize (ZmMED7_1 and ZmMED7_2). Compared with wild type, etiolated seedlings of AtMED7 RNAi silenced lines exhibited reduced hypocotyl length caused by reduced cell elongation when grown in the dark. The hypocotyl length phenotype was rescued by exogenously supplied brassinosteroid. Whole transcriptome analysis on etiolated seedlings using RNA sequencing revealed several genes known to be regulated by auxin and brassinosteroids, and a broad range of cell wall-related genes that were differentially expressed in the AtMED7 silenced lines (Kumar et al., 2018). The plant corepressor TOPLESS (TPL) is recruited to a large number of loci that are selectively induced in response to developmental or environmental cues. A potent repression domain in Helix 8 of TPL is located within the CRA domain, which directly interacts with the Mediator middle module subunits Med21 and Med10. Interactions between TPL and Mediator are required to fully repress transcription in both yeast and plants (Leydon et al., 2021).

A database of Mediator genes/proteins from many animal, fungal, and plant species can be freely accessed at  www.nipgr.ac.in/MedProDB (Bhardwaj et al., 2021)

Last updated June 2023 by John Gray

References:

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Chen H, Pugh BF. What do Transcription Factors Interact With? J Mol Biol. 2021 Jul 9;433(14):166883. doi: 10.1016/j.jmb.2021.166883. Epub 2021 Feb 20. PMID: 33621520; PMCID: PMC8184585.

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