title: Defective regulation of microRNA target genes in myoblasts from facioscapulohumeral dystrophy patients.
abstract: Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant hereditary neuromuscular disorder linked to the deletion of an integral number of 3.3-kb-long macrosatellite repeats (D4Z4) within the subtelomeric region of chromosome 4q. Most genes identified in this region are overexpressed in FSHD myoblasts, including the double homeobox genes DUX4 and DUX4c. We have carried out a simultaneous miRNome/transcriptome analysis of FSHD and control primary myoblasts. Of 365 microRNAs (miRNAs) analyzed in this study, 29 were found to be differentially expressed between FSHD and normal myoblasts. Twenty-one microRNAs (miR-1, miR-7, miR-15a, miR-22, miR-30e, miR-32, miR-107, miR-133a, miR-133b, miR-139, miR-152, miR-206, miR-223, miR-302b, miR-331, miR-362, miR-365, miR-382, miR-496, miR-532, miR-654, and miR-660) were up-regulated, and eight were down-regulated (miR-15b, miR-20b, miR-21, miR-25, miR-100, miR-155, miR-345, and miR-594). Twelve of the miRNAs up-regulated in FHSD were also up-regulated in the cells ectopically expressing DUX4c, suggesting that this gene could regulate miRNA gene transcription. The myogenic miRNAs miR-1, miR-133a, miR-133b, and miR-206 were highly expressed in FSHD myoblasts, which nonetheless did not prematurely enter myogenic differentiation. This could be accounted for by the fact that in FSHD myoblasts, functionally important target genes, including cell cycle, DNA damage, and ubiquitination-related genes, escape myogenic microRNA-induced repression.
authors.affiliation: From UMR 8126, Université Paris-Sud, CNRS, Institut de Cancérologie Gustave-Roussy, F-94805 Villejuif, France.
authors.forename: Petr
authors.initials: P
authors.lastname: Dmitriev
authors.forename: Luiza
authors.initials: L
authors.lastname: Stankevicins
authors.forename: Eugenie
authors.initials: E
authors.lastname: Ansseau
authors.forename: Andrei
authors.initials: A
authors.lastname: Petrov
authors.forename: Ana
authors.initials: A
authors.lastname: Barat
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.forename: Thomas
authors.initials: T
authors.lastname: Robert
authors.forename: Ahmed
authors.initials: A
authors.lastname: Turki
authors.forename: Vladimir
authors.initials: V
authors.lastname: Lazar
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Labourer
authors.forename: Alexandra
authors.initials: A
authors.lastname: Belayew
authors.forename: Gilles
authors.initials: G
authors.lastname: Carnac
authors.forename: Dalila
authors.initials: D
authors.lastname: Laoudj-Chenivesse
authors.forename: Marc
authors.initials: M
authors.lastname: Lipinski
authors.forename: Yegor S
authors.initials: YS
authors.lastname: Vassetzky
mesh_terms: D000328:Adult; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D024510:Muscle Development / Q000235:genetics; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D032448:Myoblasts, Skeletal / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D035683:MicroRNAs
keywords: Facioscapulohumeral Dystrophy; Genetic Diseases; MicroRNA; Muscular Dystrophy; Transcription; Transcription Regulation