Review
Mediator complexes and transcription

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Abstract

Over the past decade, various components of the transcription machinery have been identified as potential targets for activators. Recently, metazoan versions of yeast Mediator have been isolated and found to act as key coactivators to many transcription factors. Recent work has defined the composition, function and biology of metazoan mediator complexes, which has led us to propose a new nomenclature for the variously named versions of the mediator complex.

Introduction

Eukaryotic transcription is a complicated process involving a large number of factors that impose control at multiple steps. Each of these factors potentially serve as a target for regulation by DNA-bound activators or repressors [1]. Gene transcription is initiated through the recruitment of RNA polymerase II (Pol II) to the promoters of target genes and the modification of nucleosomes and remodeling of chromatin [2]. This occurs in conjunction with the assembly of multiple components of the basal transcription machinery, including the general transcription factors (GTFs) TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH 3., 4., 5.. In vitro, transcription assays can be performed using a minimum set of GTFs and purified core Pol II. However, in such in vitro assays, the core Pol II is not responsive to activators [6]. Additional factors are required to confer activator-responsive transcription [7].

The search for components required for activated transcription led to the discovery of TBP-associated factors (TAFs) in human and Drosophila systems 8., 9. and the identification of Mediator in yeast, which is defined as a complex associated with Pol II and required for transcriptional activation in vitro 10., 11.. The link between Mediator and Pol II was first suggested by the genetic isolation in yeast of suppressors of Pol II carboxy-terminal domain (CTD) truncations [12]. These Srbs (for suppressors of RNA polymerase B), together with additional factors, form the 20 subunit yeast Mediator 6., 12.. The purified Mediator complex binds to the Pol II CTD [13], and, together with core Pol II, comprises what has been termed the Pol II holoenzyme. Several additional factors have been reported to be part of the holoenzyme, including a subset of the GTFs, BRCA1 and chromatin modifying and remodeling complexes (CBP/p300, SWI/SNF) [14].

In the past decade, as investigators defined various components of the metazoan transcription machinery as targets for activators (e.g. GTFs and TAFs), the importance of Mediator was not generally appreciated. It has become clear over the past two years, however, that metazoan versions of yeast Mediator exist, and, through a convergence of findings from several laboratories, that they represent a central and required component for activation of transcription by a spectrum of regulatory proteins. This review will focus on very recent work that defines the composition, function and biology of metazoan mediator complexes. We also suggest here a new nomenclature for the variously named versions of the mediator (Table 1) as well as uniformity in subunit molecular weight assignments (Fig. 2). We will continue to refer to the original yeast complex as Mediator. We urge investigators to adopt this unified nomenclature, given the number of names and subunits for these complexes and the potential for confusion that can result from this.

Section snippets

Metazoan mediator complexes

A complex homologous to Mediator in yeast was identified in mice [15]. Independently, four laboratories, using distinct strategies, discovered large, megadalton-sized complexes in human cells that interact with a variety of transcription activators, including nuclear receptors (TRAP 16., 17•. and DRIP 18., 19••.), SREBP-1a (ARC 20., 21••.) and E1A (human Mediator [22••]), or that interact with known human Srb subunits (NAT [23] and SMCC [24••]). In addition, biochemical assays identified other

Activation and repression by mediator complexes

The transcriptional requirement for human mediator complexes has been demonstrated unambiguously in vitro. Although Mediator-D, Mediator-A, Mediator-C and Mediator-S complexes appear to exclusively coactivate transcription 19••., 21••., 22••., 27•., Mediator-N represses it and Mediator-T/S can act as both a repressor and an activator, depending on the conditions used in the cell-free transcription assay 23., 24••..

Repression of transcription by Mediator-N pointed to a possible role for CDK8, as

Other aspects of mediator function

During initiation of transcription and elongation, Pol II is transiently associated with a number of step-specific proteins and complexes [1]. For example, yeast Mediator does not bind to hyperphosphorylated Pol II [23], which suggests that it is associated with Pol II only during preinitiation and the transition to elongation (Fig. 1). Subsequently, hyperphosphorylated elongating Pol II is associated with a distinct set of elongation factors 32••., 33.. The identification of a CTD phosphatase

Roles of mediator complexes in embryonic development

Mediator homologs have also recently been identified in Schizosaccharomyces pombe, Caenorhabditis elegans and Drosophila (Table 1). Homologs of yeast Med6, Med7, Med10 and Srb7 in C. elegans form not one but two medi-ator complexes (Med6 being part of a distinct complex), both interacting with Pol II via its largest subunit [51]. These components are required in vivo for the transcriptional activation of several genes, including ceh-13 and nhr-2, during specific stages of development in the

Conclusions

The discovery of metazoan mediator complexes provides a functional and direct physical link between Pol II and activators bound to specific promoters. However, the complexity of the transcription machinery in metazoan cells provides a multiplicity of potential targets for the many subunits that constitute mediator complexes. The putative functional differences between distinct human mediator complexes, including their roles as both activators and repressors, remains to be further clarified, as

Update

Two recent papers contribute to issues discussed in this review. First, two forms of yeast Mediator, a large complex corresponding to Pol II and Mediator subunits and a smaller core complex comprising 14 Mediator subunits but lacking Pol II, Rox3, Nut1 and the Rgr1 and Srb 8-11 modules, have been isolated from yeast using affinity purification and gel filtration chromatography [59]. These results suggest that distinct Mediator complexes may exist and might be required for the activation of

Acknowledgements

The authors thank R Fisher, J Parvin, D Reinberg, and members of the Freedman lab for helpful comments and discussions. Research in our laboratory is supported by grants from the National Institutes of Health.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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