Primary AppointmentBiochemistry and Molecular Genetics
PO Box 800733
Charlottesville, VA 22908
Transcription; Chromatin Modifications, Neurodegenerative Disease, Cancer
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 that 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 four 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, including the conserved SAGA (Spt-Ada-Gcn5-Acetyltransferase) activity. 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. Our studies have expanded to the identification and characterization of other novel histone modifying complexes associated with cell cycle progression and gene expression. We are currently focused on a study of the regulation and function of a novel epigenome dedicated to protein biosynthesis and DNA replication and epigenetic mechanisms in cancer cells. An important aspect of a number of related histone-modifying complexes has been the identification of an evolutionarily conserved components which have been directly linked to factors associated with certain cancers or neurodegenerative disease. This includes the Ataxin-7 protein within the SAGA complex, which undergoes polyglutamine expansion in the debilitating neurodegenerative disease Spinocerebellar Ataxia type 7. This discovery provides a new avenue of investigation into how certain disorders may arise. Therefore, a clear understanding of how histone-modifying complexes function is vital in order to understand their role in gene activation in health and disease.