FSHD muscular dystrophy region gene 1 binds Suv4-20h1 histone methyltransferase and impairs myogenesis

• Published in: Journal of molecular cell biology 2013-10, Vol.5 (5), p.294-307
• Main Authors: Neguembor, Maria Victoria, Xynos, Alexandros, Onorati, Maria Cristina, Caccia, Roberta, Bortolanza, Sergia, Godio, Cristina, Pistoni, Mariaelena, Corona, Davide F, Schotta, Gunnar, Gabellini, Davide
• Format: Article
• Language: English
• Subjects: Animals; Caenorhabditis elegans; Carrier Proteins - metabolism; Cell Differentiation; Cell Nucleus - metabolism; Drosophila; Drosophila melanogaster - metabolism; Evolution, Molecular; Gene Knockdown Techniques; HEK293 Cells; Histone-Lysine N-Methyltransferase - metabolism; Humans; Mice; Mice, Knockout; Muscle Cells - metabolism; Muscle Cells - pathology; Muscle Development; Muscular Dystrophy, Animal - pathology; Nuclear Proteins - metabolism; Organ Specificity; Phenotype; Protein Binding; Proteins - metabolism; RNA-Binding Proteins; Xenopus laevis
• ISSN: 1674-2788; 1759-4685
• DOI: 10.1093/jmcb/mjt018

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.