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

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...

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Bibliographic Details
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
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Summary: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.
ISSN:1674-2788
1759-4685
DOI:10.1093/jmcb/mjt018