Chemical interference with DSIF complex formation lowers synthesis of mutant huntingtin gene products and curtails mutant phenotypes

Ning Deng, Yun Yun Wu, Yanan Feng, Wen Chieh Hsieh, Jen Shin Song, Yu Shiuan Lin, Ya Hsien Tseng, Wan Jhu Liao, Yi Fan Chu, Yu Cheng Liu, En Cheng Chang, Chia Rung Liu, Sheh Yi Sheu, Ming Tsan Su, Hung Chih Kuo, Stanley N. Cohen*, Tzu Hao Cheng

*此作品的通信作者

研究成果: Article同行評審

摘要

Earlier work has shown that siRNA-mediated reduction of the SUPT4H or SUPT5H proteins, which interact to form the DSIF complex and facilitate transcript elongation by RNA polymerase II (RNAPII), can decrease expression of mutant gene alleles containing nucleotide repeat expansions differentially. Using luminescence and fluorescence assays, we identified chemical compounds that interfere with the SUPT4HSUPT5H interaction and then investigated their effects on synthesis of mRNA and protein encoded by mutant alleles containing repeat expansions in the huntingtin gene (HTT), which causes the inherited neurodegenerative disorder, Huntington's Disease (HD). Here we report that such chemical interference can differentially affect expression of HTT mutant alleles, and that a prototypical chemical, 6-azauridine (6-AZA), that targets the SUPT4H-SUPT5H interaction can modify the biological response to mutant HTT gene expression. Selective and dose-dependent effects of 6-AZA on expression of HTT alleles containing nucleotide repeat expansions were seen in multiple types of cells cultured in vitro, and in a Drosophila melanogaster animal model for HD. Lowering of mutant HD protein and mitigation of the Drosophila "rough eye" phenotype associated with degeneration of photoreceptor neurons in vivo were observed. Our findings indicate that chemical interference with DSIF complex formation can decrease biochemical and phenotypic effects of nucleotide repeat expansions.

原文English
文章編號e2204779119
期刊Proceedings of the National Academy of Sciences of the United States of America
119
發行號32
DOIs
出版狀態Published - 9 8月 2022

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