title: RBFOX1 cooperates with MBNL1 to control splicing in muscle, including events altered in myotonic dystrophy type 1.
abstract: With the goal of identifying splicing alterations in myotonic dystrophy 1 (DM1) tissues that may yield insights into targets or mechanisms, we have surveyed mis-splicing events in three systems using a RT-PCR screening and validation platform. First, a transgenic mouse model expressing CUG-repeats identified splicing alterations shared with other mouse models of DM1. Second, using cell cultures from human embryonic muscle, we noted that DM1-associated splicing alterations were significantly enriched in cytoskeleton (e.g. SORBS1, TACC2, TTN, ACTN1 and DMD) and channel (e.g. KCND3 and TRPM4) genes. Third, of the splicing alterations occurring in adult DM1 tissues, one produced a dominant negative variant of the splicing regulator RBFOX1. Notably, half of the splicing events controlled by MBNL1 were co-regulated by RBFOX1, and several events in this category were mis-spliced in DM1 tissues. Our results suggest that reduced RBFOX1 activity in DM1 tissues may amplify several of the splicing alterations caused by the deficiency in MBNL1.
authors.affiliation: Department of Microbiology and Infectiology, Faculty of Medicine and Heath Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada; Laboratory of Functional Genomics, Faculty of Medicine and Heath Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Roscoe
authors.initials: R
authors.lastname: Klinck
authors.affiliation: Centre de Recherche du CHUL (Centre Hospitalier Universitaire de Québec), Université Laval, Ste-Foy, Quebec, Canada.
authors.forename: Angélique
authors.initials: A
authors.lastname: Fourrier
authors.affiliation: Laboratory of Functional Genomics, Faculty of Medicine and Heath Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Thibault
authors.affiliation: Department of Microbiology and Infectiology, Faculty of Medicine and Heath Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Johanne
authors.initials: J
authors.lastname: Toutant
authors.affiliation: Laboratory of Functional Genomics, Faculty of Medicine and Heath Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Durand
authors.affiliation: Laboratory of Functional Genomics, Faculty of Medicine and Heath Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Elvy
authors.initials: E
authors.lastname: Lapointe
authors.affiliation: Inserm UMR 837, Université Lille Nord de France, IFR114/IMPRT, Lille, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Caillet-Boudin
authors.affiliation: Inserm UMR 837, Université Lille Nord de France, IFR114/IMPRT, Lille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sergeant
authors.affiliation: Inserm U781, Hôpital Necker-EM and Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Gourdon
authors.affiliation: Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Meola
authors.affiliation: UPMC-Université Paris 06, Institute of Myology, Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Furling
authors.affiliation: Centre de Recherche du CHUL (Centre Hospitalier Universitaire de Québec), Université Laval, Ste-Foy, Quebec, Canada.
authors.forename: Jack
authors.initials: J
authors.lastname: Puymirat
authors.affiliation: Department of Microbiology and Infectiology, Faculty of Medicine and Heath Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada; Laboratory of Functional Genomics, Faculty of Medicine and Heath Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Chabot
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D000818:Animals; D002460:Cell Line; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics / Q000378:metabolism*; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*
chemical_list: C493663:MBNL1 protein, human; C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins