title: Staufen1 Regulates Multiple Alternative Splicing Events either Positively or Negatively in DM1 Indicating Its Role as a Disease Modifier.
abstract: Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by an expansion of CUG repeats in the 3' UTR of the DMPK gene. The CUG repeats form aggregates of mutant mRNA, which cause misregulation and/or sequestration of RNA-binding proteins, causing aberrant alternative splicing in cells. Previously, we showed that the multi-functional RNA-binding protein Staufen1 (Stau1) was increased in skeletal muscle of DM1 mouse models and patients. We also showed that Stau1 rescues the alternative splicing profile of pre-mRNAs, e.g. the INSR and CLC1, known to be aberrantly spliced in DM1. In order to explore further the potential of Stau1 as a therapeutic target for DM1, we first investigated the mechanism by which Stau1 regulates pre-mRNA alternative splicing. We report here that Stau1 regulates the alternative splicing of exon 11 of the human INSR via binding to Alu elements located in intron 10. Additionally, using a high-throughput RT-PCR screen, we have identified numerous Stau1-regulated alternative splicing events in both WT and DM1 myoblasts. A number of these aberrant ASEs in DM1, including INSR exon 11, are rescued by overexpression of Stau1. However, we find other ASEs in DM1 cells, where overexpression of Stau1 shifts the splicing patterns away from WT conditions. Moreover, we uncovered that Stau1-regulated ASEs harbour Alu elements in intronic regions flanking the alternative exon more than non-Stau1 targets. Taken together, these data highlight the broad impact of Stau1 as a splicing regulator and suggest that Stau1 may act as a disease modifier in DM1.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa; Centre for Neuromuscular Disease, Ottawa, Ontario, Canada.
authors.forename: Emma
authors.initials: E
authors.lastname: Bondy-Chorney
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa; Centre for Neuromuscular Disease, Ottawa, Ontario, Canada.
authors.forename: Tara E
authors.initials: TE
authors.lastname: Crawford Parks
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa; Centre for Neuromuscular Disease, Ottawa, Ontario, Canada.
authors.forename: Aymeric
authors.initials: A
authors.lastname: Ravel-Chapuis
authors.affiliation: Département de microbiologie et d'infectiologie, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Roscoe
authors.initials: R
authors.lastname: Klinck
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Lynda
authors.initials: L
authors.lastname: Rocheleau
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Pelchat
authors.affiliation: Département de microbiologie et d'infectiologie, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Chabot
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa; Centre for Neuromuscular Disease, Ottawa, Ontario, Canada.
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Jasmin
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa; Centre for Neuromuscular Disease, Ottawa, Ontario, Canada.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Côté
mesh_terms: D020413:3' Untranslated Regions; D017398:Alternative Splicing / Q000235:genetics*; D020087:Alu Elements / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology; D009223:Myotonic Dystrophy; D065636:Myotonin-Protein Kinase / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D015703:Antigens, CD; D003598:Cytoskeletal Proteins; C585517:DMPK protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C492185:STAU1 protein, human; C435941:INSR protein, human; D011972:Receptor, Insulin; D065636:Myotonin-Protein Kinase
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