University of Virginia Health System

In the eukaryotic cell nucleus, DNA is packaged by histones into nucleosomes, the repeating subunits of chromatin. This packaging of DNA strongly inhibits transcription, hampering the binding of transcriptional activators to their cognate DNA sites and inhibiting transcription elongation. A number of chromatin remodeling activities have been identified which assist transcriptional activators to overcome this barrier, by creating a localized alteration in chromatin strucutre. In addition to these activities the posttranslational acetylation of core histones has also been linked to the transcriptional capacity of chromatin for more than three decades. The acetylation of histones is catalyzed by histone acetyltransferases (HATs), which are often found to be associated with large multisubunit protein complexes that contain components with identity or homology to known regulators of transcription. In fact, a number of transcriptional coactivator proteins have now been identified as HATs, providing a direct molecular basis for the coupling of histone acetylation and transcriptional regulation. Why and how these proteins function as part of high molecular weight activities is not clearly understood however. Our research has primarily focused on the identification and characterization of native HAT / transcriptional adaptor activities from the budding yeast Saccharomyces cerevisiae and to study their role in transcriptional activation. We have isolated multiple complexes, three of which are apparently dependent upon the coactivator Gcn5 for catalytic function in vitro and transcriptional activation of target genes in vivo. We found that Gcn5 is associated with Ada or Ada and Spt proteins in native complexes, fulfilling a number of genetic predictions which had indicated that these proteins function in a common pathway. however, it seems apparent that each HAT complex may have specific attributes conferred by certain uniquely associated proteins. We have largely concentrated our research on the SAGA (Spt-Ada-Gch5-Acetyltransferase) activity, which we recently resported also contains a third group of proteins, TAFIIs. Our research objectives deal with a structural and functional dissection of the components of SAGA and other related HAT complexes. This approach is designed to investigate the multifunctionality of these complexes in their specificity of acetylation, activator and basal factor interaction, promoter selectivity and transcriptional stimulation, in order to understand their relevance to and mechanism of gene activation. An important aspect of a number of related HAT complexes has been the identification of an evolutionarily conserved component which has been directly linked to factors associated with certain cancers. This discovery provides a new avenue of investigation into how certain cancers may arise. Therefore, a clear understanding of how HAT complexes function is vital in order to understand their role in gene activation in health and disease.

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