Yeast Mediator facilitates transcription initiation at most promoters via a Tail-independent mechanism

Mediator (MED) is a conserved factor with important roles in basal and activated transcription. Here, we investigate the genome-wide roles of yeast MED by rapid depletion of its activator-binding domain (Tail) and monitoring changes in nascent transcription. Rapid Tail depletion surprisingly reduces transcription from only a small subset of genes. At most of these Tail-dependent genes, in unperturbed conditions, MED is detected at both the UASs and promoters. In contrast, at most Tail-independent genes, we find MED primarily at promoters but not at the UASs. These results suggest that MED Tail and activator-mediated MED recruitment regulates only a small subset of genes. Furthermore, we define three classes of genes that differ in PIC assembly pathways and the requirements for MED Tail, SAGA, TFIID, and BET factors Bdf1/2. Our combined results have broad implications for the roles of MED, other coactivators, and mechanisms of transcriptional regulation at different gene classes. [Display omitted] •MED Tail and activator-mediated MED recruitment regulates a small subset of genes•Transcription from only ∼6% of yeast genes is sensitive to rapid MED Tail depletion•MED binds promoters of most Tail-independent genes, bypassing the UAS•At most genes, MED functions at core promoters rather than a direct activator target Warfield et al. test the importance of transcription activator-Mediator interactions. Rapid inactivation of the MED activator-binding domain (Tail) affects expression from only ∼6% of yeast genes. At most Tail-independent genes, MED binds and acts directly at core promoters rather than as a direct activator target.