Mediator is a common target of DNA-binding transcription factors and also interacts with various components within the PIC. As a central integrator of both general and activator-specific regulatory signals, Mediator plays a prominent role in transcriptional control. Because Mediator interacts with both DNA-binding activators and the general transcriptional machinery (including RNA polymerase II), Mediator likely acts as a "molecular bridge" to link these factors and to facilitate activator-dependent regulation. Yet Mediator is clearly more than just a general "bridging" factor. In fact, Mediator appears to tailor its response in activator-specific ways. Analysis of Mediator using electron microscopy indicates that Mediator undergoes dramatic structural changes when it binds an activator. These structural changes may "activate" Mediator, but their precise mechanistic role remains undefined. Equally significant, however, is that when different activators (which regulate distinct subsets of genes) bind Mediator, they induce different conformational states in the complex. These activator-induced structural shifts may direct gene-specific regulatory events. A major focus of our lab is to understand the mechanistic role of these activator-directed conformational changes—how do they affect transcriptional activation? Do they alter Mediator interactions within the PIC? Do they trigger new Mediator-cofactor interactions?