MicroRNAs involved in molecular circuitries relevant for the Duchenne muscular dystrophy pathogenesis are controlled by the dystrophin/nNOS pathway.
In Duchenne muscular dystrophy (DMD) the absence of dystrophin at the sarcolemma delocalizes and downregulates nitric oxide synthase (nNOS); this alters S-nitrosylation of HDAC2 and its chromatin association. We show that the differential HDAC2 nitrosylation state in Duchenne versus wild-type conditions deregulates the expression of a specific subset of microRNA genes. Several circuitries controlled by the identified microRNAs, such as the one linking miR-1 to the G6PD enzyme and the redox state of cell, or miR-29 to extracellular proteins and the fibrotic process, explain some of the DMD pathogenetic traits. We also show that, at variance with other myomiRs, miR-206 escapes from the dystrophin-nNOS control being produced in activated satellite cells before dystrophin expression; in these cells, it contributes to muscle regeneration through repression of the satellite specific factor, Pax7. We conclude that the pathway activated by dystrophin/nNOS controls several important circuitries increasing the robustness of the muscle differentiation program.
Cacchiarelli
Davide
D
Institute Pasteur Cenci-Bolognetti, Department of Genetics and Molecular Biology and IBPM, "SAPIENZA" University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Martone
Julie
J
Institute Pasteur Cenci-Bolognetti, Department of Genetics and Molecular Biology and IBPM, "SAPIENZA" University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Girardi
Erika
E
Institute Pasteur Cenci-Bolognetti, Department of Genetics and Molecular Biology and IBPM, "SAPIENZA" University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Cesana
Marcella
M
Institute Pasteur Cenci-Bolognetti, Department of Genetics and Molecular Biology and IBPM, "SAPIENZA" University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Incitti
Tania
T
Institute Pasteur Cenci-Bolognetti, Department of Genetics and Molecular Biology and IBPM, "SAPIENZA" University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Morlando
Mariangela
M
Institute Pasteur Cenci-Bolognetti, Department of Genetics and Molecular Biology and IBPM, "SAPIENZA" University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Nicoletti
Carmine
C
Department of Histology and Medical Embryology, Interuniversity Institute of Myology, "SAPIENZA" University of Rome, Via A. Scarpa, 14, 00161 Rome, Italy.
Santini
Tiziana
T
Institute Pasteur Cenci-Bolognetti, Department of Genetics and Molecular Biology and IBPM, "SAPIENZA" University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Sthandier
Olga
O
Institute Pasteur Cenci-Bolognetti, Department of Genetics and Molecular Biology and IBPM, "SAPIENZA" University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Barberi
Laura
L
Department of Histology and Medical Embryology, Interuniversity Institute of Myology, "SAPIENZA" University of Rome, Via A. Scarpa, 14, 00161 Rome, Italy.
Auricchio
Alberto
A
Telethon Institute of Genetics and Medicine, Via P. Castellino 111, 80131 Napoli, Italy.
Musarò
Antonio
A
Department of Histology and Medical Embryology, Interuniversity Institute of Myology, "SAPIENZA" University of Rome, Via A. Scarpa, 14, 00161 Rome, Italy.
Bozzoni
Irene
I
Institute Pasteur Cenci-Bolognetti, Department of Genetics and Molecular Biology and IBPM, "SAPIENZA" University of Rome, P.le A. Moro 5, 00185 Rome, Italy. Electronic address: irene.bozzoni@uniroma1.it.
D000818:Animals; D016189:Dystrophin / Q000378:metabolism* / Q000502:physiology; D005786:Gene Expression Regulation; D056464:Histone Deacetylase 2 / Q000378:metabolism; D051379:Mice; D018101:Mice, Inbred mdx; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology; D009137:Muscular Dystrophy, Animal / Q000201:enzymology*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000502:physiology
D016189:Dystrophin; D035683:MicroRNAs; D052248:Nitric Oxide Synthase Type I; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2