RBFOX1 Cooperates with MBNL1 to Control Splicing in Muscle, Including Events Altered in Myotonic Dystrophy Type 1

Roscoe Klinck (1) , Angélique Fourrier (2) , Philippe Thibault (1) , Johanne Toutant (1) , Mathieu Durand (1) , Elvy Lapointe (1) , Marie-Laure Caillet-Boudin (3) , Nicolas Sergeant (3) , Geneviève Gourdon (4) , Giovanni Meola (5) , Denis Furling (6) , Jack Puymirat (2) , Benoit Chabot (1)

1 UdeS - Université de Sherbrooke
2 ULaval - Université Laval [Québec]
3 IMPRT - Institut de médecine predictive et de recherche thérapeutique
4 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
5 UNIMI - Università degli Studi di Milano = University of Milan
6 Institut de Myologie

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.

Domaines: Médecine humaine et pathologie

Roscoe Klinck, Angélique Fourrier, Philippe Thibault, Johanne Toutant, Mathieu Durand, et al.. RBFOX1 Cooperates with MBNL1 to Control Splicing in Muscle, Including Events Altered in Myotonic Dystrophy Type 1. PLoS ONE, 2014, 9 (9), pp.e107324. ⟨10.1371/journal.pone.0107324⟩. ⟨hal-01365880⟩