Facioscapulohumeral muscular dystrophy region gene 1 over-expression causes primary defects of myogenic stem cells.

Journal of Cell Science (Impact Factor: 5.43). 03/2013; 126(10). DOI: 10.1242/jcs.121533
Source: PubMed


Over-expression of FSHD Region Gene 1 (FRG1) in mice, frogs and worms leads to muscular and vascular abnormalities. Nevertheless, the mechanism that follows FRG1 over-expression and finally leads to muscular defects is currently unknown. Here, we show that the earliest phenotype displayed by FRG1 mice is a postnatal muscle-growth defect. Long before the development of muscular dystrophy, FRG1 mice exhibit also a muscle regeneration impairment. Ex-vivo and in-vivo experiments revealed that FRG1 over-expression causes myogenic stem-cell activation, proliferative, clonogenic and differentiation defects. A comparative gene expression profiling of WT and FRG1 muscles from young pre-dystrophic mice identified differentially expressed genes in several gene categories and networks that could explain the emerging tissue and myogenic stem-cell defects. Overall, our study provides new insights in the pathways regulated by FRG1 and suggests that muscle-stem cells defects could contribute to the pathology of FRG1 mice.

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Available from: Elia Stupka
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    ABSTRACT: Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy with a strong epigenetic component. It is associated with deletion of a macrosatellite repeat leading to over-expression of the nearby genes. Among them, we focused on FSHD region gene 1 (FRG1) since its over-expression in mice, Xenopus laevis and Caenorhabditis elegans, leads to muscular dystrophy-like defects, suggesting that FRG1 plays a relevant role in muscle biology. Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. Moreover, Suv4-20h KO mice develop muscular dystrophy signs. Finally, we identify the FRG1/Suv4-20h1 target Eid3 as a novel myogenic inhibitor that contributes to the muscle differentiation defects. Our study suggests a novel role of FRG1 as epigenetic regulator of muscle differentiation and indicates that Suv4-20h1 has a gene-specific function in myogenesis.
    Full-text · Article · May 2013 · Journal of Molecular Cell Biology
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    ABSTRACT: Facioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is characterized by atrophy and weakness of selective muscle groups. FSHD is considered an autosomal dominant disease with incomplete penetrance and unpredictable variability of clinical expression within families. Mice over-expressing FRG1 (FSHD region gene 1), a candidate gene for this disease, develop a progressive myopathy with features of the human disorder. Here we show that in FRG1 over-expressing mice, fast muscles, which are the most affected by the dystrophic process, display anomalous fast skeletal troponin T (fTnT) isoform resulting from the aberrant splicing of the Tnnt3 mRNA that precedes the appearance of dystrophic signs. We determine that muscles of FRG1 mice develop less strength due to impaired contractile properties of fast-twitch fibers associated with an anomalous MyHC/actin ratio and a reduced sensitivity to Ca2+. We demonstrate that the decrease of Ca2+ sensitivity of fast-twitch fibers depends on the anomalous troponin complex and can be rescued by the substitution with the wild-type proteins. Finally, we find that the presence of aberrant splicing isoforms of TNNT3 characterizes dystrophic muscles in FSHD patients. Collectively, our results suggest that anomalous TNNT3 profile correlates with the muscle impairment in both humans and mice. On the basis of these results, we propose that aberrant fTnT represents a biological marker of muscle phenotype severity and disease progression.
    Preview · Article · Dec 2013 · AJP Regulatory Integrative and Comparative Physiology
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    ABSTRACT: RNA-binding proteins (RBP) contribute to gene regulation through post-transcriptional events. Despite the important roles demonstrated for several RBP in regulating skeletal myogenesis in vitro, very few RBP coding genes have been characterized during skeletal myogenesis in vertebrate embryo. In the present study we report that Rbm24, which encodes the RNA-binding motif protein 24, is required for skeletal muscle differentiation in vivo. We show that Rbm24 transcripts are expressed at all sites of skeletal muscle formation during embryogenesis of different vertebrates, including axial, limb and head muscles. Interestingly, we find that Rbm24 protein starts to accumulate in MyoD-positive myoblasts and is transiently expressed at the onset of muscle cell differentiation. It accumulates in myotomal and limb myogenic cells, but not in Pax3-positive progenitor cells. Rbm24 expression is under the direct regulation by MyoD, as demonstrated by in vivo chromatin immunoprecipitation assay. Using morpholino knockdown approach, we further show that Rbm24 is required for somitic myogenic progenitor cells to differentiate into muscle cells during chick somitic myogenesis. Altogether, these results highlight Rbm24 as a novel key regulator of the myogenic differentiation program during vertebrate development.
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