title: FSHD muscular dystrophy region gene 1 binds Suv4-20h1 histone methyltransferase and impairs myogenesis.
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.
authors.affiliation: Dulbecco Telethon Institute and Division of Regenerative Medicine, San Raffaele Scientific Institute, 20132 Milano, Italy.
authors.forename: Maria Victoria
authors.initials: MV
authors.lastname: Neguembor
authors.forename: Alexandros
authors.initials: A
authors.lastname: Xynos
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Onorati
authors.forename: Roberta
authors.initials: R
authors.lastname: Caccia
authors.forename: Sergia
authors.initials: S
authors.lastname: Bortolanza
authors.forename: Cristina
authors.initials: C
authors.lastname: Godio
authors.forename: Mariaelena
authors.initials: M
authors.lastname: Pistoni
authors.forename: Davide F
authors.initials: DF
authors.lastname: Corona
authors.forename: Gunnar
authors.initials: G
authors.lastname: Schotta
authors.forename: Davide
authors.initials: D
authors.lastname: Gabellini
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism; D019143:Evolution, Molecular; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins; D032342:Muscle Cells / Q000378:metabolism / Q000473:pathology; D024510:Muscle Development; D009137:Muscular Dystrophy, Animal / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D009928:Organ Specificity; D010641:Phenotype; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D016601:RNA-Binding Proteins
chemical_list: D002352:Carrier Proteins; C101270:FRG1 protein, human; C484440:Frg1 protein, mouse; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; C570043:Suv4-20h protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C542918:KMT5C protein, human
keywords: D4Z4; H4K20; KMT5B; SUV4-20H1; chromatin; copy number variation; muscle differentiation