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Altered transcription in yeast expressing expanded polyglutamine.
1Division of Medical Genetics, Department of Medicine, University of Washington, Box 357360, Seattle, WA 98195, USA.
Summary
Expanded polyglutamine tracts cause neurodegenerative diseases. Yeast models show this toxicity involves transcriptional dysregulation, which can be reversed by histone deacetylase inhibitors, suggesting new therapeutic strategies.
Area of Science:
- Molecular biology
- Neurogenetics
- Yeast genetics
Background:
- Expanded polyglutamine tracts are implicated in fatal neurodegenerative diseases.
- Transcriptional dysregulation occurs early in polyglutamine pathogenesis, potentially via interaction with histone acetyltransferases.
Purpose of the Study:
- To investigate if polyglutamine-mediated transcriptional dysregulation occurs in yeast.
- To explore the role of the Spt/Ada/Gcn5 acetyltransferase (SAGA) complex in polyglutamine toxicity.
- To assess the potential of histone deacetylase inhibitors as a therapeutic strategy.
Main Methods:
- Expressing proteins with expanded polyglutamine tracts in Saccharomyces cerevisiae.
- Analyzing gene expression profiles using DNA microarrays.
- Performing reporter gene assays and assessing toxicity in yeast deletion strains.
Main Results:
- Expanded polyglutamine induced chaperone and heat-shock factor genes in yeast.
- Nuclear expanded polyglutamine caused transcriptional repression, mimicking SAGA complex deletions.
- Histone deacetylase inhibitor Trichostatin A mitigated polyglutamine-mediated repression of the PHO84 gene promoter.
Conclusions:
- Transcriptional dysregulation is a conserved early feature of polyglutamine toxicity in yeast.
- Polyglutamine toxicity is linked to the SAGA complex.
- Histone deacetylase inhibitors show potential for treating polyglutamine diseases.