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This mutation triggers cellular and biochemical pathologies, leading to cognitive, motor, and psychiatric symptoms in HD patients. Targeting HTT splicing with small molecule drugs is a compelling approach to lowering HTT protein levels to treat HD, and splice modulators are currently being tested in the clinic. Here, we identify PRMT5 as a novel regulator of HTT messenger RNA (mRNA) splicing and alternative polyadenylation. PRMT5 inhibition disrupts the splicing of HTT introns 9 and 10, leading to the activation of multiple proximal intronic polyadenylation sites within these introns and promoting premature termination, cleavage, and polyadenylation of the HTT mRNA. This suggests that HTT protein levels may be lowered due to this mechanism. We also detected increasing levels of these truncated HTT transcripts across a series of neuronal differentiation samples, which correlated with lower PRMT5 expression. Notably, PRMT5 inhibition in glioblastoma stem cells potently induced neuronal differentiation. We posit that PRMT5-mediated regulation of intronic polyadenylation, premature termination, and cleavage of the HTT mRNA modulates HTT expression and plays an important role during neuronal differentiation.<\/jats:p>","DOI":"10.1093\/nar\/gkaf347","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T09:24:45Z","timestamp":1746005085000},"source":"Crossref","is-referenced-by-count":4,"title":["PRMT5 promotes full-length <i>HTT<\/i> expression by repressing multiple proximal intronic polyadenylation sites"],"prefix":"10.1093","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6559-7774","authenticated-orcid":false,"given":"Manisha","family":"Yadav","sequence":"first","affiliation":[{"name":"University of Toronto Department of Medical Biophysics, , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]},{"name":"Princess Margaret Cancer Centre, U , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]},{"name":"niversity Health Network , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona\u00a0A","family":"AlQazzaz","sequence":"additional","affiliation":[{"name":"Structural Genomics Consortium, , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]},{"name":"University of Toronto , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0076-8824","authenticated-orcid":false,"given":"Felipe\u00a0E","family":"Ciamponi","sequence":"additional","affiliation":[{"name":"Center for Molecular Biology and Genetic Engineering, University of Campinas (UNICAMP) , Campinas 13083-872,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolene\u00a0C","family":"Ho","sequence":"additional","affiliation":[{"name":"Structural Genomics Consortium, , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]},{"name":"University of Toronto , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxim\u00a0I","family":"Maron","sequence":"additional","affiliation":[{"name":"Albert Einstein College of Medicine Department of Biochemistry, , Bronx, NY 10461 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiden\u00a0M","family":"Sababi","sequence":"additional","affiliation":[{"name":"Donnelly Centre for Cellular and Biomolecular Research, University of Toronto , Toronto , ON, M5S3E1,\u00a0","place":["Canada"]},{"name":"University of Toronto Department of Molecular Genetics, , Toronto , ON, M5S3E1,\u00a0","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"MacLeod","sequence":"additional","affiliation":[{"name":"Donnelly Centre for Cellular and Biomolecular Research, University of Toronto , Toronto , ON, 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of Medicine, Nanyang Technological University , 636921,","place":["Singapore"]},{"name":"School of Biosciences, Cardiff University , Cardiff CF103AX ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"S\u00e1nchez-Osuna","sequence":"additional","affiliation":[{"name":"Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al , Montreal , QC, H3C3J7,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patty","family":"Sachamitr","sequence":"additional","affiliation":[{"name":"Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumor Research Centre , The Hospital for Sick Children, Toronto , ON, M5G0A4,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Kushida","sequence":"additional","affiliation":[{"name":"Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumor 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M5S3M2,\u00a0","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter\u00a0B","family":"Dirks","sequence":"additional","affiliation":[{"name":"Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children , Toronto , ON, M5G0A4,","place":["Canada"]},{"name":"Division of Neurosurgery , Department of Surgery, University of Toronto, Toronto , ON,\u00a0M5S1A8,","place":["Canada"]},{"name":"University of Toronto Department of Laboratory Medicine and Pathobiology, , Toronto , ON M5S1A8,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0185-8861","authenticated-orcid":false,"given":"Gary\u00a0D","family":"Bader","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, U , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]},{"name":"niversity Health Network , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]},{"name":"Donnelly Centre for Cellular and Biomolecular Research, University of Toronto , Toronto , ON, M5S3E1,\u00a0","place":["Canada"]},{"name":"University of Toronto Department of Molecular Genetics, , Toronto , ON, M5S3E1,\u00a0","place":["Canada"]},{"name":"Lunenfeld-Tanenbaum Research Institut , Toronto , ON, M5G1X5,\u00a0","place":["Canada"]},{"name":"e, Sinai Health System , Toronto , ON, M5G1X5,\u00a0","place":["Canada"]},{"name":"University of Toronto Department of Computer Science, , ON, M5S3E1,\u00a0","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2542-6641","authenticated-orcid":false,"given":"Ray","family":"Truant","sequence":"additional","affiliation":[{"name":"McMaster University Department of Biochemistry and Biomedical Sciences, , Hamilton , ON L8N3Z5 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6390-2560","authenticated-orcid":false,"given":"Katlin\u00a0B","family":"Massirer","sequence":"additional","affiliation":[{"name":"Center for Molecular Biology and Genetic Engineering, University of Campinas (UNICAMP) , Campinas 13083-872,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6560-9621","authenticated-orcid":false,"given":"Dalia","family":"Barsyte-Lovejoy","sequence":"additional","affiliation":[{"name":"Structural Genomics Consortium, , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]},{"name":"University of Toronto , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]},{"name":"University of Toronto Department of Pharmacology and Toxicology, , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Shechter","sequence":"additional","affiliation":[{"name":"Albert Einstein College of Medicine Department of Biochemistry, , Bronx, NY 10461 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel\u00a0J","family":"Harding","sequence":"additional","affiliation":[{"name":"Structural Genomics Consortium, , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]},{"name":"University of Toronto , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]},{"name":"Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto , ON, M5S3M2,\u00a0","place":["Canada"]},{"name":"University of Toronto Department of Pharmacology and Toxicology, , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl\u00a0H","family":"Arrowsmith","sequence":"additional","affiliation":[{"name":"University of Toronto Department of Medical Biophysics, , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]},{"name":"Princess Margaret Cancer Centre, U , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]},{"name":"niversity Health Network , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]},{"name":"Structural Genomics Consortium, , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]},{"name":"University of Toronto , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8785-7856","authenticated-orcid":false,"given":"Panagiotis","family":"Prinos","sequence":"additional","affiliation":[{"name":"Structural Genomics Consortium, , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]},{"name":"University of Toronto , Toronto , ON, M5G1L7,\u00a0","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"2025050706452214200_B1","doi-asserted-by":"publisher","first-page":"15005","DOI":"10.1038\/nrdp.2015.5","article-title":"Huntington disease","volume":"1","author":"Bates","year":"2015","journal-title":"Nat Rev Dis Primers"},{"key":"2025050706452214200_B2","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1080\/13696998.2022.2033493","article-title":"Epidemiology and economic burden of Huntington\u2019s disease: a Canadian provincial public health system perspective","volume":"25","author":"Shaw","year":"2022","journal-title":"J Med Econ"},{"key":"2025050706452214200_B3","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s40734-018-0069-3","article-title":"Atrophy of the putamen at time of clinical motor onset in Huntington\u2019s disease: a 6-year follow-up study","volume":"5","author":"Coppen","year":"2018","journal-title":"J Clin Mov Disord"},{"key":"2025050706452214200_B4","doi-asserted-by":"publisher","first-page":"4408","DOI":"10.1038\/s41598-017-01510-z","article-title":"The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington\u2019s disease patients","volume":"7","author":"Neueder","year":"2017","journal-title":"Sci Rep"},{"key":"2025050706452214200_B5","doi-asserted-by":"publisher","first-page":"4408","DOI":"10.1093\/brain\/awad353","article-title":"Unravelling the role of huntingtin: from neurodevelopment to neurodegeneration","volume":"146","author":"Schultz","year":"2023","journal-title":"Brain"},{"key":"2025050706452214200_B6","doi-asserted-by":"publisher","first-page":"7299","DOI":"10.1038\/s41467-021-27157-z","article-title":"Small molecule splicing modifiers with systemic HTT-lowering activity","volume":"12","author":"Bhattacharyya","year":"2021","journal-title":"Nat 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