Altered transcription in yeast expressing expanded polyglutamine

Expanded polyglutamine tracts are responsible for at least eight fatal neur odegenerative diseases. in mouse models, proteins with expanded polyglutami ne cause transcriptional dysregulation before onset of symptoms, suggesting that this dysregulation may be an early event in polyglutamine pathogenesi s. Transcriptional dysregulation and cellular toxicity may be due to intera ction between expanded polyglutamine and the histone acetyltransferase CREB -binding protein. To determine whether polyglutamine-mediated transcription al dysregulation occurs in yeast, we expressed polyglutamine tracts in Sacc haromyces cerevisiae. Gene expression profiles were determined for strains expressing either a cytoplasmic or nuclear protein with 23 or 75 glutamines , and these profiles were compared to existing profiles of mutant yeast str ains. Transcriptional induction of genes encoding chaperones and heat-shock factors was caused by expression of expanded polyglutamine in either the n ucleus or cytoplasm. Transcriptional repression was most prominent in yeast expressing nuclear expanded polyglutamine and was similar to profiles of y east strains deleted for components of the histone acetyltransferase comple x Spt/Ada/Gcn5 acetyltransferase (SAGA). The promoter from one affected gen e (PHO84) was repressed by expanded polyglutamine in a reporter gene assay, and this effect was mitigated by the histone deacetylase inhibitor, Tricho statin A. Consistent with an effect on SAGA, nuclear expanded polyglutamine enhanced the toxicity of a deletion in the SAGA component SPT3. Thus, an e arly component of polyglutamine toxicity, transcriptional dysregulation, is conserved in yeast and is pharmacologically antagonized by a histone deace tylase inhibitor. These results suggest a therapeutic approach for treatmen t of polyglutamine diseases and provide the potential for yeast-based scree ns for agents that reverse polyglutamine toxicity.