1. FSHD muscular dystrophy region gene 1 binds Suv4-20h1 histone methyltransferase and impairs myogenesis
- Author
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Cristina Godio, Alexandros Xynos, Gunnar Schotta, Maria Victoria Neguembor, Mariaelena Pistoni, Davide Gabellini, Roberta Caccia, Davide Corona, Sergia Bortolanza, Maria Cristina Onorati, Neguembor MV, Xynos A, Onorati MC, Caccia R, Bortolanza S, Godio C, Pistoni M, Corona D, Schotta G, and Gabellini D
- Subjects
Muscle Development ,Evolution, Molecular ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Genetics ,medicine ,Facioscapulohumeral muscular dystrophy ,Myocyte ,Animals ,Humans ,Epigenetics ,Muscular dystrophy ,Myopathy ,Molecular Biology ,030304 developmental biology ,Cell Nucleus ,Mice, Knockout ,0303 health sciences ,Muscle Cells ,biology ,Myogenesis ,Microfilament Proteins ,Nuclear Proteins ,Proteins ,RNA-Binding Proteins ,Cell Differentiation ,Cell Biology ,General Medicine ,Histone-Lysine N-Methyltransferase ,Muscular Dystrophy, Animal ,medicine.disease ,Molecular biology ,Histone ,Drosophila melanogaster ,HEK293 Cells ,Phenotype ,Organ Specificity ,Histone methyltransferase ,Epigenetic deregulation by FRG1 ,Gene Knockdown Techniques ,biology.protein ,medicine.symptom ,Carrier Proteins ,030217 neurology & neurosurgery ,Protein Binding - 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.
- Published
- 2013