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.
Highlights
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by the overexpression of double homeobox genes DUX4 and DUX4c
We have previously shown that the D4Z4 repeats contain a potent transcriptional enhancer [25, 26], which interacts with the Kruppel-like transcription factor KLF15 and activates the expression of DUX4c and FRG2 genes [27]
Identification of miRNA Differentially Expressed in FSHD— miRNA expression profiles in total RNA extracted from primary myoblast populations originating from four FSHD patients and four normal individuals were compared using a high throughput TaqMan qRT-PCR approach
Summary
FSHD is characterized by the overexpression of double homeobox genes DUX4 and DUX4c. Results: We found 29 miRNAs differentially expressed between FSHD and normal myoblasts. DUX4 is generally considered as an FSHD inducer gene, other genes might contribute to the pathological phenotype: FRG1, FRG2 (FSHD region genes 1 and 2), ANT1 (adenine nucleotide translocator), and DUX4c (double homeobox 4, centromeric) Most of these genes have been shown to be up-regulated in skeletal muscle tissue of some FSHD patients and primary myoblasts derived from them (for a review, see Ref. 6). We have analyzed miRNA expression in primary myoblasts from healthy subjects and FSHD patients and found 29 miRNAs differentially expressed in FSHD samples Twelve of these miRNAs, including myogenic microRNAs miR-1, miR206, miR-133a, and miR-133b were induced by DUX4c overexpression, suggesting that DUX4c is a novel regulator of miRNA expression. The expression analysis of target genes of these miRNAs revealed that some of them are not repressed by myogenic miRNAs in FSHD cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
