PRMT5 promotes full-length <i>HTT</i> expression by repressing multiple proximal intronic polyadenylation sites

Expansion of the CAG trinucleotide repeat tract in exon 1 of the Huntingtin (HTT) gene causes Huntington's disease (HD) through the expression of a polyglutamine-expanded form of the HTT protein. 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.

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Publication Details

Journal
Nucleic Acids Research
Published
2025-04-22
DOI
https://doi.org/10.1093/nar/gkaf347
Citations
1
Primary Topic
Cancer-related gene regulation
Type
article
Field-Weighted Citation Impact
0.81

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article

PRMT5 promotes full-length HTT expression by repressing multiple proximal intronic polyadenylation sites

María Sánchez‐Osuna, Laura M. Richards, Moloud Ahmadi, Gary D. Bader et al.
1 citations
Nucleic Acids Research
Cancer-related gene regulation
0.81
article

PRMT5 promotes full-length HTT expression by repressing multiple proximal intronic polyadenylation sites

María Sánchez‐Osuna, Laura M. Richards, Moloud Ahmadi, Gary D. Bader, C.H. Arrowsmith, Graham MacLeod, Maxim I. Maron, Katlin B. Massirer, Dalia Baršytė-Lovejoy, Ray Truant, Rebecca Kurtz, Stéphane Angers, Jolene Caifeng Ho, Michelle Kushida, Rachel Harding, Mona Alqazzaz, Mike Tyers, David Shechter, Sarah R. Langley, Panagiotis Prinos, Vincent Tano, Costanza Ferrari Bardile, Garrett Bullivant, Trevor J. Pugh, Aiden M Sababi, Patty Sachamitr, Mahmoud A. Pouladi, Felipe E. Ciamponi, Manisha Yadav, Peter Dirks
article en
1 citations

Abstract

Expansion of the CAG trinucleotide repeat tract in exon 1 of the Huntingtin (HTT) gene causes Huntington's disease (HD) through the expression of a polyglutamine-expanded form of the HTT protein. 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.

Nucleic Acids ResearchVol. 53(8)
Ontario Institute for Cancer Research (CA), Albert Einstein College of Medicine (US), University Health Network (CA), 3M (United States) (US), University of British Columbia (CA), Nanyang Technological University (SG), Universidade Estadual de Campinas (UNICAMP) (BR), University of Toronto (CA), Lunenfeld-Tanenbaum Research Institute (CA), Hospital for Sick Children (CA), Princess Margaret Cancer Centre (CA), Health Net (US), Structural Genomics Consortium (CA), Institute for Research in Immunology and Cancer (CA), Brain Tumour Research (GB), SickKids Foundation (CA), Cellular Research (United States) (US), BC Children's Hospital (CA), Biologie du Développement et Cellules Souches (FR), Université de Montréal (CA), Cardiff University (GB), McMaster University (CA)
American Association for Cancer Research, Boehringer Ingelheim, Genentech Foundation, Pfizer, Bayer, Entertainment Industry Foundation, Irma T. Hirschl Trust, Takeda Pharmaceuticals U.S.A., Genome Canada, Merck KGaA, Ontario Institute for Cancer Research, Government of Ontario, Stand Up To Cancer Canada, Ontario Genomics Institute, Mitacs, National Institutes of Health, Bristol-Myers Squibb Canada, Canadian Institutes of Health Research, Janssen Biotech
Good health and well-being
Openalex Percentile: Top 29%
Cancer-related gene regulation
0.81
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