ENHANCER FUNCTION

Cold Spring Harbor Laboratory, Cold Spg Hbr NY

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Abstract

Oncogenic transformation involves chances in gene expression that frequently result from changes in transcriptional regulation. Transcription is accomplished by one of three RNA polymerases, RNA polymerase I, II, or III. Their activity is generally controlled by the combined impact of multiple sequence-specific transcription factors on the basal transcriptional apparatus. Whereas the basal transcription factors are positioned near the transcriptional start site, sequence-specific activators can be positioned far from the transcriptional start site at distal enhancers. The activators that bind enhancers are generally modular in structure, consisting of DNA- binding domains that are responsible for targeting the transcription factor to the appropriate cis-regulatory element and activation domains that are responsible for stimulating transcription once tethered to the enhancer by the DNA-binding domain. In our previous studies, we have shown that activation domains can have a profound influence on the promoter specificity of transcriptional activation by distinguishing among different arrangements of basal promoter elements found in messenger RNA (mRNA) and small nuclear RNA (snRNA) promoters. The goal of this project is to understand the basic mechanisms by which sequence-specific activators stimulate transcription. To accomplish this goal, we contrast and compare the activities of activation domains in both mRNA- and snRNA-promoter contexts. We will (I) elucidate the mechanisms of activator-basal machinery interactions in mRNA promoters and (ii) determine the mechanisms of snRNA promoter activation. In a new line of research, we will also characterize transcription of the gene encoding the RNA component of telomerase, the enzyme that catalyzes the synthesis of telomeres at the ends of chromosomes.