In the eukaryotic cell nucleus, DMA is packaged by histones into nucleosomes, the repeating subunits of chromatin. The regulation of gene expression from chromatin involves the action of chromatin modifying activities including histone acetlytransferases (HATs). HAT enzymes are frequently associated with large multiprotein coactivator complexes that contain other transcriptional regulators. These observations have provided a direct molecular basis for the coupling of histone acetylation and the regulation of transcription. HAT proteins are known to associate with cellular oncoproteins and tumor suppressor proteins and have been described in certain translocations associated with leukemias and thus have been postulated to play a central role in the etiology cancer as well as viral infection and nuclear hormone receptor action. SAGA (Spt- Ada-Gcn5 Acetyltransferase) and SLIK (SAGA-Like) are 2 homologous and highly conserved multi-subunit HAT complexes that were originally identified in Saccharomyces cerevisiae. We have identified the protein Sgf73/ySca7, a homologue of the human protein ataxin-7, as a component of SAGA and SLIK. In its pathological form, this protein is responsible for the neurodegenerative disease spinocerebellar ataxia 7 (SCA7). Yeast Sca7 is necessary for the integrity and function of both SAGA and SLIK and a polyglutamine expanded version of human Sca7 assembles a SAGA complex that is specifically deficient in nucleosome acetylation. These observations have significant implications for the function of the human Sca7 protein in disease pathogenesis. The goals of this proposal are to use yeast, mammalian cell lines and mice as models to elucidate the mechanism behind the pathology of the SCA7 disorder.
The Specific Aims are to determine the function of Sca7 protein, to examine the biochemical consequences of polyglutamine expansion on function of the SAGA family of complexes in histone modification and transcriptional regulation and test the hypothesis that depletion of GCN5 function in the CMS and retina contributes to SCA7 pathology in a mouse model. By identifying the physiological roles of these proteins it may be possible to gain insight as to how pathological alleles coding for proteins with polyglutamine tracts promote disease progression. Furthermore we aim to investigate the use of histone deacetylase inhibitors for the treatement of cellular dysfunction as a consequence SCA7 expansion. This, in turn, may suggest possible therapeutic treatments for this and other trinucleotide repeat diseases, such as Huntington's disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CDIN-D (01))
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Gwinn, Katrina
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University of Virginia
Schools of Medicine
United States
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Burke, Tara L; Miller, Jaime L; Grant, Patrick A (2013) Direct inhibition of Gcn5 protein catalytic activity by polyglutamine-expanded ataxin-7. J Biol Chem 288:34266-75
Chen, Yi Chun; Gatchel, Jennifer R; Lewis, Rebecca W et al. (2012) Gcn5 loss-of-function accelerates cerebellar and retinal degeneration in a SCA7 mouse model. Hum Mol Genet 21:394-405
McCullough, Shaun D; Xu, Xiaojiang; Dent, Sharon Y R et al. (2012) Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes. Proc Natl Acad Sci U S A 109:21319-24
Stolzenberg, Danielle S; Grant, Patrick A; Bekiranov, Stefan (2011) Epigenetic methodologies for behavioral scientists. Horm Behav 59:407-16
McCullough, Shaun D; Grant, Patrick A (2010) Histone acetylation, acetyltransferases, and ataxia--alteration of histone acetylation and chromatin dynamics is implicated in the pathogenesis of polyglutamine-expansion disorders. Adv Protein Chem Struct Biol 79:165-203
Tsai, Houng-Wei; Grant, Patrick A; Rissman, Emilie F (2009) Sex differences in histone modifications in the neonatal mouse brain. Epigenetics 4:47-53
Baker, S P; Grant, P A (2007) The SAGA continues: expanding the cellular role of a transcriptional co-activator complex. Oncogene 26:5329-40
Daniel, Jeremy A; Grant, Patrick A (2007) Multi-tasking on chromatin with the SAGA coactivator complexes. Mutat Res 618:135-48