Mechanisms of transcriptional regulation and transcription factor specificity

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Summary Precise regulation of transcription is required for many cellular processes and misregulation of gene expression is linked to many human diseases. In prior work, great progress has been made in identifying important mechanisms and principles of transcriptional regulation. With this background, and using new technologies and approaches, this is an excellent time to tackle the next set of fundamental problems in gene regulation that have been difficult to address in prior work. Two related and important questions in the transcription field are: what are the primary mechanisms of gene regulation by sequence-specific transcription factors? and, how do these factors cooperate to orchestrate transcription of cellular genes? To address these questions, we will focus on three areas involving transcription factor and coactivator specificity and the activation mechanisms used at many genes: (i) Mechanisms leading to the genome-wide specificities of the coactivators TFIID and SAGA. Differential use of these coactivators defines two fundamental gene classes that dictate the mechanisms of preinitiation complex (PIC) assembly and the response to transcription factors and chromatin. (ii) The gene-specific functions of the coactivator Mediator in transcriptional regulation. At least two distinct pathways are used by transcription factors to modulate Mediator function that are transcription factor and promoter-specific, but the molecular basis of these mechanisms is not well understood. (iii) Mechanisms of transcription activator specificity and function. We will broaden our current studies on the function of acidic activation domains to examine mechanisms used by other widely used activator types and to examine how transcription factors bound at native UAS/enhancer elements cooperate. To address these fundamental problems, as in past work, we will use a combination of methods and technologies that include molecular, biochemical, genomic, computational, and structural approaches. In combination with our strong preliminary results, these new approaches and directions will reveal important conserved mechanisms and principles that illustrate how transcription factors, coactivators, chromatin, and the basal transcription machinery work together to modulate genome-wide transcription.