{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:37:21Z","timestamp":1781105841275,"version":"3.54.1"},"reference-count":62,"publisher":"National Academy of Sciences","issue":"32","license":[{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,8,9]]},"abstract":"<jats:p>\n                    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 (\n                    <jats:italic>HTT<\/jats:italic>\n                    ), which causes the inherited neurodegenerative disorder, Huntington\u2019s Disease (HD). Here we report that such chemical interference can differentially affect expression of\n                    <jats:italic>HTT<\/jats:italic>\n                    mutant alleles, and that a prototypical chemical, 6-azauridine (6-AZA), that targets the SUPT4H-SUPT5H interaction can modify the biological response to mutant\n                    <jats:italic>HTT<\/jats:italic>\n                    gene expression. Selective and dose-dependent effects of 6-AZA on expression of\n                    <jats:italic>HTT<\/jats:italic>\n                    alleles containing nucleotide repeat expansions were seen in multiple types of cells cultured in\u00a0vitro, and in a\n                    <jats:italic>Drosophila melanogaster<\/jats:italic>\n                    animal model for HD. Lowering of mutant HD protein and mitigation of the\n                    <jats:italic>Drosophila<\/jats:italic>\n                    \u201crough eye\u201d phenotype associated with degeneration of photoreceptor neurons in\u00a0vivo were observed. Our findings indicate that chemical interference with DSIF complex formation can decrease biochemical and phenotypic effects of nucleotide repeat expansions.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2204779119","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T15:22:29Z","timestamp":1659367349000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":11,"title":["Chemical interference with DSIF complex formation lowers synthesis of mutant huntingtin gene products and curtails mutant phenotypes"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1321-5508","authenticated-orcid":false,"given":"Ning","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA 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Taipei, 11221, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Fan","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Life Science and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4669-2586","authenticated-orcid":false,"given":"Yu-Cheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3828-3918","authenticated-orcid":false,"given":"En-Cheng","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, 11221, 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