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The Mediator complex: a central integrator of transcription

Key Points

  • A basic function of the Mediator complex is to communicate regulatory signals from DNA-binding transcription factors (TFs) directly to RNA polymerase II (Pol II).

  • Different TFs, and the signalling pathways that regulate these TFs, often interact with different Mediator subunits to regulate expression of their target genes.

  • Mediator is composed of a large number of subunits, some of which can reversibly associate with Mediator or are expressed at variable levels in different cell types.

  • Mediator binding to various proteins and protein complexes, such as TFs, Pol II and the cyclin-dependent kinase 8 (CDK8) module, results in large-scale structural changes. These structural changes, in turn, appear to modulate the function of Mediator and may affect its ability to bind to other proteins.

  • Because of its direct and extensive interactions with Pol II, Mediator regulates multiple stages of Pol II transcription (for example, initiation and re-initiation). Mediator interactions with the super elongation complex (SEC) also seem to be important for its regulation of Pol II elongation.

  • The interactions between TFs, Mediator, cohesin and the pre-initiation complex (PIC) correlate with the formation of enhancer–promoter DNA loops, which are an important regulatory mechanism. Interactions between Mediator and non-coding RNA also correlate with DNA looping.

Abstract

The RNA polymerase II (Pol II) enzyme transcribes all protein-coding and most non-coding RNA genes and is globally regulated by Mediator — a large, conformationally flexible protein complex with a variable subunit composition (for example, a four-subunit cyclin-dependent kinase 8 module can reversibly associate with it). These biochemical characteristics are fundamentally important for Mediator's ability to control various processes that are important for transcription, including the organization of chromatin architecture and the regulation of Pol II pre-initiation, initiation, re-initiation, pausing and elongation. Although Mediator exists in all eukaryotes, a variety of Mediator functions seem to be specific to metazoans, which is indicative of more diverse regulatory requirements.

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Figure 1: Structural changes in Mediator control its interactions with other transcription regulators.
Figure 2: A simplified model for Mediator-dependent regulation of multiple stages of RNA polymerase II transcription.
Figure 3: Mediator regulates chromatin architecture.
Figure 4: Mediator as an end point of signalling cascades.

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Acknowledgements

The authors thank A. Shilatifard and the reviewers for comments on the manuscript. They apologize that they could not discuss other important and relevant research owing to space and citation limits. D.J.T.'s laboratory is supported by the US National Science Foundation (MCB-1244175) and the US National Cancer Institute (CA175849; CA1707041; CA175448). B.L.A. has been supported in part by the US National Institutes of Health (T32 GM08759).

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Sequence conservation between yeast and human Mediator (PDF 546 kb)

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Glossary

Mediator complex

(Also known as core Mediator). The 21-subunit (Saccharomyces cerevisiae) or 26-subunit (human) complex that does not contain the cyclin-dependent kinase 8 module.

Enhancer–promoter gene looping

Looping of genomic DNA that juxtaposes an enhancer, which may be dozens (or more) of kilobases away, and a promoter.

Cyclin-dependent kinase 8 module

(CDK8 module). A group of four subunits, CDK8, CCNC, MED12 and MED13, that can reversibly associate with Mediator.

CDK8–Mediator

Mediator bound to the four-subunit cyclin-dependent kinase 8 (CDK8) module; in metazoans, this complex lacks the MED26 subunit.

Intrinsically disordered regions

(IDRs). Protein sequences that do not adopt a fixed 3D structure, yet may do so upon binding to another protein.

Uterine leiomyomas

Benign tumours of smooth muscle cells originating from the uterus.

Head module

The yeast Mediator subunits Med6, Med8, Med11, Med17, Med18, Med19, Med20 and Med22.

Middle module

The yeast Mediator subunits Med1, Med4, Med7, Med9, Med10, Med21 and Med31.

Tail module

The yeast Mediator subunits Med2, Med3, Med5, Med14, Med15 and Med16.

Crystal structure docking

Fitting an existing crystal structure into a larger structural model.

Open complex

An RNA polymerase II complex in which double-stranded DNA is unwound to single-stranded DNA around the transcription start site; an open complex is required to initiate transcription.

CTD repeats

A series of YSPTSPS repeats within the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II.

Chromatin immunoprecipitation followed by sequencing

(ChIP–seq). Immunoprecipitation of a protein followed by DNA sequencing to determine the binding sites of the protein throughout the genome.

Sequential chromatin immunoprecipitation

(ChIP–reChIP). Two sequential ChIP experiments designed to determine the co-occupancy of two different proteins at or around the same DNA sequence.

Operons

Groups of genes that are sequentially arranged in the genome and that are under the control of a single promoter.

Pericentromeric heterochromatin

Heterochromatin regions near chromosomal centromeres; the primary sites of sister chromatid cohesion.

Telomeric heterochromatin

Heterochromatin regions near telomeres, which are repetitive regions of DNA at the ends of chromosomes.

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Allen, B., Taatjes, D. The Mediator complex: a central integrator of transcription. Nat Rev Mol Cell Biol 16, 155–166 (2015). https://doi.org/10.1038/nrm3951

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