Transcriptional profiling in facioscapulohumeral muscular dystrophy to identify candidate biomarkers

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive neuromuscular disorder caused by contractions of repetitive elements within the macrosatellite D4Z4 on chromosome 4q35. The pathophysiology of FSHD is unknown and, as a result, there is currently no effective treatment available for this disease. To better understand the pathophysiology of FSHD and develop mRNA-based biomarkers of affected muscles, we compared global analysis of gene expression in two distinct muscles obtained from a large number of FSHD subjects and their unaffected first-degree relatives. Gene expression in two muscle types was analyzed using GeneChip Gene 1.0 ST arrays: biceps, which typically shows an early and severe disease involvement; and deltoid, which is relatively uninvolved. For both muscle types, the expression differences were mild: using relaxed cutoffs for differential expression (fold change ≥1.2; nominal P value <0.01), we identified 191 and 110 genes differentially expressed between affected and control samples of biceps and deltoid muscle tissues, respectively, with 29 genes in common. Controlling for a false-discovery rate of <0.25 reduced the number of differentially expressed genes in biceps to 188 and in deltoid to 7. Expression levels of 15 genes altered in this study were used as a "molecular signature" in a validation study of an additional 26 subjects and predicted them as FSHD or control with 90% accuracy based on biceps and 80% accuracy based on deltoids.skeletal muscle | microarray

SORBS2transcription is activated by telomere position effect–over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy

“…Due to the complexity of SORBS2 (42 exons, 118 putative transcripts), previous results are often contradictory, with some observing up-regulation (Celegato et al 2006), and others reporting no change in the expression of this gene (Masny et al 2010;Rahimov et al 2012). These results are not surprising if the major changes involve modifications of the splicing pattern rather than a global change in the transcription level.…”

β - catenin is central to DUX4 -driven network rewiring in facioscapulohumeral muscular dystrophy

“…Actin cytoskeleletal signalling has also been implicated in FSHD pathology [15]. Our work shows perturbed crosstalk between such signalling and HIF1-a may contribute to FSHD.…”

“…Indeed, it was recently demonstrated that DUX4 drives over half the differentially expressed transcripts in FSHD [18]. However, the number of differentially expressed transcripts is very low in FSHD as compared with other pathologies [18,5,15] and it has been shown that a more subtle transcriptional dysregulation may better represent unifying features of FSHD [15]. Our FSHD network captures such subtle dysregulation and it was important to determine whether the network, derived from unbiased meta-analysis of multiple muscle biopsies from FSHD patients, could be controlled by DUX4.…”

“…TP53 [16], JUNB [20,17], HIF1A [20], WNT3 [4], LMO3 [20], ANXA4 [5] and HSPB1 [22]. Gene Set Enrichment Analysis (GSEA) [23] on the intersection also implicated many FSHD associated processes, such as myogenesis [17] and regulation of the actin cytoskeleton [15], and pathways, including, p53 [16], Wnt [4], and VEGF [5] To identify genes implicated as rewiring specifically in FSHD, we also ran InSpiRe on two datasets each describing skeletal muscle gene expression during ageing (GSE5086 [24] and GSE9676 [25]), disuse atrophy (GSE5110 [26] and GSE8872 [27]) and other muscle diseases involving inflammation and wasting (GSE3307 [19], where juvenile dermatomyositis and limb-girdle muscular dystrophy type 2A datasets were independently analysed). Genes rewiring in these non-FSHD datasets were considered as secondary rewiring.…”

Clinical Immunology and Multiplex Biomarkers of Human Tuberculosis

“…Fluidigm, for example, provides high-throughput real-time quantitative PCR based on proprietary microfluidic chips (Rahimov et al 2012). These gene expression assays are commercially available, but they are still costly and require specialized equipment not routinely available in laboratories in most TB-endemic areas.…”