title: In Vitro and In Vivo Modulation of Alternative Splicing by the Biguanide Metformin.
abstract: Major physiological changes are governed by alternative splicing of RNA, and its misregulation may lead to specific diseases. With the use of a genome-wide approach, we show here that this splicing step can be modified by medication and demonstrate the effects of the biguanide metformin, on alternative splicing. The mechanism of action involves AMPK activation and downregulation of the RBM3 RNA-binding protein. The effects of metformin treatment were tested on myotonic dystrophy type I (DM1), a multisystemic disease considered to be a spliceopathy. We show that this drug promotes a corrective effect on several splicing defects associated with DM1 in derivatives of human embryonic stem cells carrying the causal mutation of DM1 as well as in primary myoblasts derived from patients. The biological effects of metformin were shown to be compatible with typical therapeutic dosages in a clinical investigation involving diabetic patients. The drug appears to act as a modifier of alternative splicing of a subset of genes and may therefore have novel therapeutic potential for many more diseases besides those directly linked to defective alternative splicing.
authors.affiliation: CECS/AFM, Evry Cedex, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Laustriat
authors.affiliation: CECS/AFM, Evry Cedex, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Gide
authors.affiliation: CECS/AFM, Evry Cedex, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Barrault
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, Centre Léon Bérard, Lyon, France.|Université Lyon 1, CNRS, UMR 5558, INRIA Bamboo, Villeurbanne, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Chautard
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, Centre Léon Bérard, Lyon, France.
authors.forename: Clara
authors.initials: C
authors.lastname: Benoit
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, Centre Léon Bérard, Lyon, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Auboeuf
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Boland
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Battail
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors.forename: François
authors.initials: F
authors.lastname: Artiguenave
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Deleuze
authors.affiliation: INSERM UMR 1141, Hôpital Robert Debré, Paris, France.|Université Paris 7, Faculté de Médecine Denis Diderot, Paris, France.
authors.forename: Paule
authors.initials: P
authors.lastname: Bénit
authors.affiliation: INSERM UMR 1141, Hôpital Robert Debré, Paris, France.|Université Paris 7, Faculté de Médecine Denis Diderot, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.affiliation: Centre Hospitalier Sud Francilien and CERITD, Evry Cedex, France.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Franc
authors.affiliation: Centre Hospitalier Sud Francilien and CERITD, Evry Cedex, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Charpentier
authors.affiliation: Sorbonne Universités, UPMC Université Paris 06, Centre de Recherche en Myologie, INSERM UMRS974, CNRS FRE3617, Institut de Myologie, Paris 75013, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Furling
authors.affiliation: GH Henri Mondor, Inserm U955, Université Paris Est, Créteil, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bassez
authors.affiliation: CECS/AFM, Evry Cedex, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Nissan
authors.affiliation: INSERM/UEVE UMR 861, Evry Cedex, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Martinat
authors.affiliation: INSERM/UEVE UMR 861, Evry Cedex, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Peschanski
authors.affiliation: INSERM/UEVE UMR 861, Evry Cedex, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Baghdoyan