Spt4 is Selectively Required for Transcription of Extended Trinucleotide Repeats

• Main Authors: Chia-Rung Liu, 劉珈榮
• Other Authors: Tzu-Hao Cheng
• Format: Others
• Language: zh-TW
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/18616238140828112548

博士 === 國立陽明大學 === 生化暨分子生物研究所 === 100 === Huntington’s disease (HD), a neuronal degenerative disorder, is caused by expanded CAG repeats at the 5’ end of Htt gene. The expanded CAG repeats encode a long stretch of polyglutamine (polyQ), which has propensity to induce protein aggregation and results in neuronal toxicity. Besides HD, 8 other neurodegenerative diseases are also caused by polyQ expansion and they are classified as polyQ diseases. In this study, we established an assay platform that reveals the solubility of polyQ protein by monitoring the colors of yeast cells. Through genome-wide genetic screening, a mutation in transcription elongation factor Spt4 was identified which selectively reduced the expression and aggregation of proteins containing extended polyQ. Spt4 enhances processivity of RNA polymerase II by preventing its dissociation during transcription elongation through expanded CAG regions. Spt4 also regulates the expression of genes with other types of tri-nucleotide repeat in coding regions, as well as in untranslated regions (UTR). In mammalian neuron cells, down-regulation of Supt4h, the yeast SPT4 ortholog, leads to decreased expression and aggregation of polyQ proteins. Cellular toxicity caused by aggregation of polyQ is also attenuated. Analysis by RNA Sequencing reveals limited effects of Supt4h down-regulation on overall gene expression. These results establish that Supt4h is a potential target for the treatment of polyQ diseases.