? The genome of an organism encodes thousands of genes that must be appropriately expressed for normal cellular functioning. A thorough understanding of the mechanistic details of genome-wide transcriptional control is important, as dozens of transcription factors have been implicated in the etiology of many human diseases including cancer. Transcription factors, as well as their mechanisms of function, are highly conserved between yeast and mammals. This proposal is aimed at generating a genome-wide, detailed, and systematic molecular understanding of transcriptional regulation in yeast during specific physiological responses. A functional genomic approach will be used to study the transcriptional reprogramming of the yeast genome during the responses to heat shock and stationary phase stress. For selected transcription factors that mediate stress responses in yeast, their downstream targets will be determined using a variety of approaches. The relative influence of chromatin structure and binding site complexity on transcriptional specificity will be determined. Simultaneously, we will apply a variety of computational methods to organize, analyze and interpret the large body of resulting data. They will be directed towards identifying functional transcriptional regulatory networks underlying global responses, as well as identifying cis-regulatory elements and aspects of chromatin structure that confer specificity. Regulatory networks will be modelled, experimentally validated, and extended to explain global transcriptional profiles. This work will test several hypotheses about genome-wide transcriptional regulation, including i) global transcriptional programs can be reconstructed in terms of their composite transcriptional pathways and networks mediated by individual transcriptional regulators ii) transcriptional specificity is achieved through a combination of cis-regulatory elements and local chromatin structure at promoters, iii) different members of multi-subunit complexes may have distinct roles in mediating transcriptional responses. Given the conservation of transcription factors and mechanisms between yeast and mammals, the results are likely to be significant in understanding and further studying transcriptional control in the human genome. ? ?
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