FSHD muscular dystrophy Region Gene 1 binds Suv4-20h1 histone methyltransferase and impairs myogenesis

Facioscapulohumeral Muscular Dystrophy (FSHD) is an autosomal dominant myopathywith a strong epigenetic component. It is associated with deletion of a macrosatellite repeat leadingto over-expression of the nearby genes. Among them, we focused on FSHD Region Gene 1 (FRG1)since its over-expression in mice, X. laevis and C. elegans leads to muscular dystrophy-like defects,suggesting that FRG1 plays a relevant role in muscle biology. Here we show that, when overexpressed,FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdowninhibits myogenesis. Moreover, Suv4-20h KO mice develop muscular dystrophy signs. Finally, weidentify the FRG1/Suv4-20h1 target Eid3 as a novel myogenic inhibitor that contributes to themuscle differentiation defects. Our study suggests a novel role of FRG1 as epigenetic regulator ofmuscle differentiation and indicates that Suv4-20h1 has a gene-specific function in myogenesis.