title: Multi-level omics analysis in a murine model of dystrophin loss and therapeutic restoration.
abstract: Duchenne muscular dystrophy (DMD) is a classical monogenic disorder, a model disease for genomic studies and a priority candidate for regenerative medicine and gene therapy. Although the genetic cause of DMD is well known, the molecular pathogenesis of disease and the response to therapy are incompletely understood. Here, we describe analyses of protein, mRNA and microRNA expression in the tibialis anterior of the mdx mouse model of DMD. Notably, 3272 proteins were quantifiable and 525 identified as differentially expressed in mdx muscle (P < 0.01). Therapeutic restoration of dystrophin by exon skipping induced widespread shifts in protein and mRNA expression towards wild-type expression levels, whereas the miRNome was largely unaffected. Comparison analyses between datasets showed that protein and mRNA ratios were only weakly correlated (r = 0.405), and identified a multitude of differentially affected cellular pathways, upstream regulators and predicted miRNA-target interactions. This study provides fundamental new insights into gene expression and regulation in dystrophic muscle.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK, Sanford Burnham Prebys Medical Discovery Institute, Development, Aging and Regeneration Program, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Roberts
authors.affiliation: Department of Oncology/Pathology, Cancer Proteomics Mass Spectrometry, SciLifeLab Stockholm, Karolinska Institutet, Stockholm SE-171 21, Sweden.
authors.forename: Henrik J
authors.initials: HJ
authors.lastname: Johansson
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: McClorey
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Godfrey
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Huddinge SE-141 86, Sweden and.
authors.forename: K Emelie M
authors.initials: KE
authors.lastname: Blomberg
authors.affiliation: Laboratory of Molecular Biology, Medical Research Council, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Thibault
authors.initials: T
authors.lastname: Coursindel
authors.affiliation: Laboratory of Molecular Biology, Medical Research Council, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gait
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Huddinge SE-141 86, Sweden and.
authors.forename: C I Edvard
authors.initials: CI
authors.lastname: Smith
authors.affiliation: Department of Oncology/Pathology, Cancer Proteomics Mass Spectrometry, SciLifeLab Stockholm, Karolinska Institutet, Stockholm SE-171 21, Sweden.
authors.forename: Janne
authors.initials: J
authors.lastname: Lehtiö
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK, Department of Laboratory Medicine, Karolinska Institutet, Huddinge SE-141 86, Sweden and.
authors.forename: Samir
authors.initials: S
authors.lastname: El Andaloussi
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK, matthew.wood@dpag.ox.ac.uk.
authors.forename: Matthew J A
authors.initials: MJ
authors.lastname: Wood
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics*; D020869:Gene Expression Profiling; D015316:Genetic Therapy; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D035683:MicroRNAs / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D009154:Mutation; D040901:Proteomics; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D016189:Dystrophin; D035683:MicroRNAs; D012333:RNA, Messenger