Hughes et al. wanted to test their hypothesis that, at least in part, the cellular process by which polyQ tracts damage neurons is cell-autonomous and conserved, and therefore might occur in yeast much like it does in striatal neurons of people with Huntington's. To do so, they expressed polyQ tracts of different lengths in yeast, targeted some to the cytoplasm and other to the nucleus, and analyzed with DNA microarrays how these tracts affect gene expression. When they compared the pattern of gene expression changes to those of existing yeast mutants, they found that the polyQ-induced pattern resembled that of a strain deleted for components of the histone acetyltransferase complex. However, compensating for the loss of this chromatin-modifying enzyme activity by inhibiting its counterpart, histone deacetylase, reduced the effect polyQ had on gene expression.

These data support previous work implicating transcriptional cofactors that act via histone acetylation in a polyglutamine disease model of Drosophila (Fernandez-Funez, et al. 2000).

The 35 genes that were upregulated in response to polyQ tracts included 14 genes involved in protein folding, suggesting that polyglutamine expansions induce a mild heat-shock response, write the authors. Intriguingly, the chaperone most highly expressed is also required for prion propagation. Of the 25 genes repressed by polyQ tracts, 10 encode small molecule transporters and 10 others encode proteins involved in phosphate metabolism.-Gabrielle Strobel.

Reference:Hughes RE, Lo RS, Davis C, Strand AD, Neal CL, Olson JM, Fields S. Altered transcription in yeast expressing expanded polyglutamine. Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13201-6. Abstract