Core Promoter-selective Transcription by RNA Polymerase II

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Intellectulal Merit. Expression of eukaryotic genes is regulated at the transcriptional level by sequence-specific DNA-binding regulators that control the assembly and activity of the general/basal RNA polymerase II transcription machinery at the "core promoter". The core promoter encompasses the transcription initiation site of the gene and is composed of various core promoter DNA elements including the TATA box, the Initiator and other elements that are variably present in different genes. These DNA elements control not only the strength of the core promoter but also the selective response of the core promoter to specific enhancers and transcription regulators and therefore play a critical role in the regulation of differential gene expression. Recent analyses have revealed the conservation and prevalence of the Initiator element in eukaryotic gene core promoters from yeast to humans. However, the functions of the Initiator and the mechanisms of TATA-Initiator synergy, have remained poorly understood. This project will characterize the mechanisms of Initiator function and TATA-Initiator synergy and the roles of transcription factors and recently identified cofactors in Initiator-dependent gene transcription in vitro and in vivo. Mechanistic analyses will be performed in reconstituted transcription reactions in vitro, and gene-selective transcription functions in vivo will be analyzed by a number of approaches. The results promise to transform our understanding of the one of the most fundamental processes involved in regulation of gene expression in eukaryotes. Broader Impacts. This project will enhance the infrastructure of research and training through the continued instruction of undergraduate and graduate students and mentoring of postdoctoral researchers. The research integrates into the PI's long-term interest in mammalian gene regulation and will be synergistic with his teaching responsibilities. Results and generated tools will be communicated and made available to the scientific community via research publications and through discussions in scientific meetings, and to broader audiences via the internet. The PI is committed to increase the participation of underrepresented minorities in science and will continue to engage minority students in research through established minority access programs at the University of California at Riverside.