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The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation

Key Points

  • The metazoan Mediator is a multiprotein complex of about 30 subunits that seems to have key roles in the regulation of essentially all genes. Many of the individual subunits and the overall structural organization of the complex, which consists of multiple modules ('head', 'middle', 'tail' and 'kinase') are evolutionarily conserved from yeast to human.

  • Numerous transcriptional activators and repressors, which carry signals from various physiological pathways, target distinct Mediator subunits. Most (although not all) of these subunits reside in the tail or the kinase modules.

  • Mediator also interacts with RNA polymerase II (Pol II). A primary mechanism whereby Mediator fulfils a co-activator role, therefore, is to recruit Pol II to the promoter on interaction with the appropriate activator.

  • Mediator can also modulate the functions of some of the components of the components of the Pol II general transcription machinery.

  • Beyond promoting recruitment of the initiation machinery to the promoter, evidence is mounting for post-recruitment roles for Mediator that might even regulate transcription elongation by Pol II.

  • Mediator is also involved in coordinating the function of other co-activators, especially those involved in establishing transcription complexes on chromatin templates.

  • In addition to its roles in promoting activated transcription, Mediator can repress transcription in some contexts, primarily through diverse mechanisms that entail the kinase module. In one documented case, this module is crucial for the establishment of a developmentally important silenced epigenetic state of a gene.

  • Overall, recent evidence suggests that Mediator is not simply a binary switch that turns transcription on or off but rather a centre for integrating the regulatory programmes of genes.

Abstract

The Mediator is an evolutionarily conserved, multiprotein complex that is a key regulator of protein-coding genes. In metazoan cells, multiple pathways that are responsible for homeostasis, cell growth and differentiation converge on the Mediator through transcriptional activators and repressors that target one or more of the almost 30 subunits of this complex. Besides interacting directly with RNA polymerase II, Mediator has multiple functions and can interact with and coordinate the action of numerous other co-activators and co-repressors, including those acting at the level of chromatin. These interactions ultimately allow the Mediator to deliver outputs that range from maximal activation of genes to modulation of basal transcription to long-term epigenetic silencing.

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Figure 1: Involvement of Mediator in multiple steps of transcription.
Figure 2: Modular structure of Mediator and interactions with diverse factors.
Figure 3: Modulation of Mediator function by ancillary factors: coordination of chromatin remodelling and PIC formation.
Figure 4: Modulation of Mediator function by ancillary factors: epigenetic silencing.

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Acknowledgements

We apologize to colleagues whose work could not be cited directly owing to limitations of scope and space. We thank members of our laboratory for their many contributions to our understanding of the Mediator. Our work on the Mediator is supported in part by NIH grant 1RC1GM09029 to S.M. and R.G.R.

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Correspondence to Sohail Malik.

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Glossary

Pre-initiation complex

The multiprotein assembly containing Pol II and the general transcription factors, TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH, that forms at core promoter elements before the onset of transcription. It is formally analogous to the 'closed complex' described for the prokaryotic RNA polymerase.

Chromatin

The nucleoprotein structure that packages DNA in the nucleus of eukaryotic cells. The basic unit of chromatin is the nucleosome, a protein core made up of two molecules each of histones H2A, H2B, H3 and H4, around which 146 bp of DNA is wrapped. Different chromatin states are defined by a range of post-translational modifications of core histones and by the incorporation of various histone isoforms.

Basal transcription

Low levels of transcription that can occur in the absence of an activator, especially in in vitro systems.

Initiation

The step in the transcription cycle in which Pol II in the PIC synthesizes the first phophodiester bond. It takes place subsequent to promoter melting or open complex formation.

Chromatin remodelling

Typically an ATP-dependent enzymatic process that alters histone–DNA interactions or regulates the position of nucleosomes.

Chromatin modification

Includes covalent modification (acetylation, phosphorylation, methylation and ubiquitylation) of histones on discrete residues.

Elongation

Refers to the phase in the transcription cycle in which the polymerase that has escaped the promoter extends oligomeric RNA chains into full-length products.

Promoter escape

The events in the transcription cycle that lead to relinquishing of multiple interactions holding the PIC together and entry of Pol II into the elongation phase of transcription.

Capping

The process by which eukaryotic mRNA is modified by the addition of an m7G(5′)ppp(5′)N structure at the 5′ terminus. Capping is essential for several important steps of gene expression, including mRNA stabilization, splicing, mRNA export from the nucleus and initiation of translation.

Enhancer

A regulatory DNA element that usually binds several transcription factors and can activate transcription from a promoter at relatively large distances and in an orientation-independent manner.

Core promoter

The regulatory region of a gene that specifies the transcription start site and on to which Pol II and the general transcription factors assemble to initiate transcription. Depending on the promoter, core promoter sequence elements vary and may extend from approximately 40 bp upstream (for example, the TATA box) to more than 40 bp downstream of the transcription start site.

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Malik, S., Roeder, R. The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation. Nat Rev Genet 11, 761–772 (2010). https://doi.org/10.1038/nrg2901

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