Two related multisubunit complexes, TFIID and SAGA, serve similar roles in eukaryotic transcriptional regulation. Both have multiple shared activities including regulation of the TATA binding protein TBP. They differ in that TFIID contributes more to TATA-Iess """"""""housekeeping"""""""" gene expression, whereas SAGA contributes more to TATA-containing stress-induced gene expression. The first specific aim of this research is to determine how promoters discriminate between TFIID and SAGA in Saccharomyces cerevisiae. This will be accomplished by altering the affinity of candidate specificity determinant (promoter elements, acetylation states, bromodomains) and determining whether genome-wide transcriptional dependency on TFIID versus SAGA is altered.
In aim 2, models developed from in vivo studies will be tested in defined biochemical assays, allowing TFIID and SAGA to compete for binding to a limiting amount of immobilized target, and assessing which is preferentially bound. TFIID has many enzymatic and binding activities that reside in two subunits, TAF1 and Bdfl. The third specific aim will focus on assessing the contribution of each of these activities to the expression of all genes. Specific domains of these proteins will be inactivated and gene expression assayed with DNA microarrays. Bioinformatic comparisons with other genome-wide studies will provide insight into the functions of specific TFIID domains in the genome-wide regulatory network. TAF1 has histone acetyltransferase (HAT) activity, which might be functionally redundant with other HAT complexes, as has been shown with Gcn5. The fourth specific aim is to determine whether other HATs compensate for TAF1 throughout the genome. Genome-wide expression studies will be performed on HAT mutants in the presence and absence of TAF1 HAT mutants. Patterns of gene expression changes will provide insight into the functional relationship between TAF1 and other HATs. This research focuses on fundamental mechanisms of eukaryotic gene regulation. When proper regulation is altered, diseases often arise. A greater understanding of the workings of the transcription machinery provide a strong foundation for developing therapeutic methods to intercede in the mis-expression of genes.
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