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

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Abstract
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.