The human Mediator complex is a large (> 1.0 MDa), multi-subunit protein complex that is generally required to control expression of protein-coding genes.  Mediator is present from yeast to human, but the amino acid sequence of each individual Mediator subunit has diverged considerably throughout evolution. In fact, of all of the components of the general transcription machinery (TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH, and RNA polymerase II), Mediator is the most poorly conserved. However, many similarities in function exist between the human and yeast Mediator complexes; therefore, the wealth of information gained from studies of yeast Mediator have been extremely valuable for understanding how the human complex works to regulate gene expression.

Because proper regulation of transcription is so critical to prevent tumor formation and a host of other potential disorders, humans have evolved elaborate mechanisms by which the spatial and temporal patterns of gene expression are controlled. Indeed, a profusion of regulatory proteins and RNA elements work together in various capacities and contexts to help maintain proper transcriptional control. Regulatory proteins include sequence-specific DNA-binding transcription factors (a.k.a. activators), components of the general transcription machinery, various classes of cofactors, and a variety of chromatin remodeling/modifying enzyme complexes. Despite the structural and functional diversity of this regulatory machinery, only a select few components-RNA polymerase II (pol II), TFIIH, and Mediator-are considered "master regulators" of transcription; that is, they affect transcription of all or nearly all protein-coding genes. Among these, comparatively little is known about Mediator because, in contrast to pol II or TFIIH, Mediator has only been discovered in humans relatively recently and its roles in transcriptional control are poorly understood.

Currently, it is believed that Mediator controls transcription by mediating signals between DNA-binding activator and the core transcriptional machinery (see the Figure). This is based upon several experimental observations. First, Mediator is a general target of DNA-binding activators. Second, Mediator is capable of several direct interactions with pol II and can form a tight, binary complex with the pol II enzyme. Because Mediator binds directly to pol II and is also a general target of DNA-binding transcription factors, Mediator likely acts as a "molecular bridge" for communicating regulatory signals between activators and the pol II enzyme. Our lab is working to identify the molecular mechanisms by which this communication occurs-that is, how Mediator interactions with activators and the transcriptional machinery are controlled, and how they may positively or negatively influence gene expression.