title: The Krüppel-like factor 15 as a molecular link between myogenic factors and a chromosome 4q transcriptional enhancer implicated in facioscapulohumeral dystrophy.
abstract: Facioscapulohumeral muscular dystrophy (FSHD), a dominant hereditary disease with a prevalence of 7 per 100,000 individuals, is associated with a partial deletion in the subtelomeric D4Z4 repeat array on chromosome 4q. The D4Z4 repeat contains a strong transcriptional enhancer that activates promoters of several FSHD-related genes. We report here that the enhancer within the D4Z4 repeat binds the Krüppel-like factor KLF15. KLF15 was found to be up-regulated during myogenic differentiation induced by serum starvation or by overexpression of the myogenic differentiation factor MYOD. When overexpressed, KLF15 activated the D4Z4 enhancer and led to overexpression of DUX4c (Double homeobox 4, centromeric) and FRG2 (FSHD region gene 2) genes, whereas its silencing caused inactivation of the D4Z4 enhancer. In immortalized human myoblasts, the D4Z4 enhancer was activated by the myogenic factor MYOD, an effect that was abolished upon KLF15 silencing or when the KLF15-binding sites within the D4Z4 enhancer were mutated, indicating that the myogenesis-related activation of the D4Z4 enhancer was mediated by KLF15. KLF15 and several myogenesis-related factors were found to be expressed at higher levels in myoblasts, myotubes, and muscle biopsies from FSHD patients than in healthy controls. We propose that KLF15 serves as a molecular link between myogenic factors and the activity of the D4Z4 enhancer, and it thus contributes to the overexpression of the DUX4c and FRG2 genes during normal myogenic differentiation and in FSHD.
authors.affiliation: CNRS UMR8126, Université Paris-Sud 11, Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France.
authors.forename: Petr
authors.initials: P
authors.lastname: Dmitriev
authors.forename: Andrei
authors.initials: A
authors.lastname: Petrov
authors.forename: Eugenie
authors.initials: E
authors.lastname: Ansseau
authors.forename: Luiza
authors.initials: L
authors.lastname: Stankevicins
authors.forename: Sébastien
authors.initials: S
authors.lastname: Charron
authors.forename: Elena
authors.initials: E
authors.lastname: Kim
authors.forename: Tomas Jan
authors.initials: TJ
authors.lastname: Bos
authors.forename: Thomas
authors.initials: T
authors.lastname: Robert
authors.forename: Ahmed
authors.initials: A
authors.lastname: Turki
authors.forename: Frédérique
authors.initials: F
authors.lastname: Coppée
authors.forename: Alexandra
authors.initials: A
authors.lastname: Belayew
authors.forename: Vladimir
authors.initials: V
authors.lastname: Lazar
authors.forename: Gilles
authors.initials: G
authors.lastname: Carnac
authors.forename: Dalila
authors.initials: D
authors.lastname: Laoudj
authors.forename: Marc
authors.initials: M
authors.lastname: Lipinski
authors.forename: Yegor S
authors.initials: YS
authors.lastname: Vassetzky
mesh_terms: D000818:Animals; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D024510:Muscle Development / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C499414:FRG2 protein, human; C414172:KLF15 protein, human; C467418:Klf15 protein, mouse; D051741:Kruppel-Like Transcription Factors; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D009687:Nuclear Proteins; D014157:Transcription Factors