Chemical interference with DSIF complex formation lowers synthesis of mutant huntingtin gene products and curtails mutant phenotypes
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 SUPT4H-SUPT5H 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:119 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 119(2022), 32 vom: 09. Aug., Seite e2204779119 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Deng, Ning [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 03.08.2022 Date Revised 02.02.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2204779119 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Chemical interference with DSIF complex formation lowers synthesis of mutant huntingtin gene products and curtails mutant phenotypes |
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| 500 | |a Date Completed 03.08.2022 | ||
| 500 | |a Date Revised 02.02.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 SUPT4H-SUPT5H 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a DSIF | |
| 650 | 4 | |a Huntington’s disease | |
| 650 | 4 | |a SUPT4H | |
| 650 | 4 | |a Spt4 | |
| 650 | 4 | |a nucleotide repeats | |
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| 650 | 7 | |a Huntingtin Protein |2 NLM | |
| 650 | 7 | |a Mutant Proteins |2 NLM | |
| 650 | 7 | |a Nuclear Proteins |2 NLM | |
| 650 | 7 | |a Repressor Proteins |2 NLM | |
| 650 | 7 | |a SUPT4H1 protein, human |2 NLM | |
| 650 | 7 | |a SUPT5H protein, human |2 NLM | |
| 650 | 7 | |a Transcriptional Elongation Factors |2 NLM | |
| 650 | 7 | |a Azauridine |2 NLM | |
| 650 | 7 | |a 7BVB29RCPR |2 NLM | |
| 700 | 1 | |a Wu, Yun-Yun |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Yanan |e verfasserin |4 aut | |
| 700 | 1 | |a Hsieh, Wen-Chieh |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Jen-Shin |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Yu-Shiuan |e verfasserin |4 aut | |
| 700 | 1 | |a Tseng, Ya-Hsien |e verfasserin |4 aut | |
| 700 | 1 | |a Liao, Wan-Jhu |e verfasserin |4 aut | |
| 700 | 1 | |a Chu, Yi-Fan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yu-Cheng |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, En-Cheng |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Chia-Rung |e verfasserin |4 aut | |
| 700 | 1 | |a Sheu, Sheh-Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Su, Ming-Tsan |e verfasserin |4 aut | |
| 700 | 1 | |a Kuo, Hung-Chih |e verfasserin |4 aut | |
| 700 | 1 | |a Cohen, Stanley N |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Tzu-Hao |e verfasserin |4 aut | |
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