RNA-seq of FSHD and control immortalised myoblasts I
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE102812 | GEO | 2017/08/19
SECONDARY ACCESSION(S): PRJNA399103
REPOSITORIES: GEO
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Project description:RNA-seq of FSHD and control immortalised myoblasts II
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Project description:The gene expression pathways leading to muscle pathology in facioscapulohumeral dystrophy (FSHD) remain to be elucidated. This muscular dystrophy is caused by a contraction of an array of tandem 3.3-kb repeats (D4Z4) at 4q35.2. We compared expression of control and FSHD myoblasts and myotubes (three preparations each) on exon microarrays (Affymetrix Human Exon 1.0 ST) and validated FSHD-specific differences for representative genes by qRT-PCR on additional myoblast cell strains. The FSHD and control myoblasts used for these experiments were shown to grow and differentiate into myotubes equally efficiently as control myoblasts. There were no significant FSHD-control differences in RNA levels for MYOD1 and MYOG at the myoblast and myotube stages and for MYF5 and MYF6 at the myoblast stage. In contrast, 295 other genes were dysregulated at least 2-fold in FSHD vs. control myoblasts (p <0.01, adjusted for multiple comparisons). Remarkably, only 10% of the FSHD-associated gene dysregulation at the myoblast stage was downregulation. At the myotube stage, about ten times as many genes exhibited FSHD-associated downregulated as at the myoblast stage and twice as many genes displayed FSHD-associated upregulation. The FSHD-related changes in RNA levels appear to be due to posttranscriptional as well as transcriptional alterations. Among the prominently dysregulated pathways were signaling and oxidative stress pathways. By comparing expression profiles of control myoblasts and myotubes to each other and to 19 non-muscle cell types profiled identically, our study also revealed many new myogenesis associations for genes not previously annotated as muscle-specific. Keywords: Disease state analysis and time course for differentiation
2011-09-29 | GSE26145 | GEO
Project description:Proteomic studies in facioscapulohumeral muscular dystrophy (FSHD) could offer new insight to disease mechanisms underpinned by post-transcriptional processes. We used stable isotope (deuterium oxide; D2O) labelling and peptide mass spectrometry to investigate the abundance and turnover rates of proteins in cultured muscle cells from 2 individuals affected by FSHD and their unaffected siblings (UASb). We measured the abundance of 4483 proteins and the turnover rate of 2324 proteins in each (n = 4) myoblast sample. FSHD myoblasts exhibited a greater abundance but slower turnover rate of subunits of mitochondrial respiratory complexes and mitochondrial ribosomal proteins, which may indicate an accumulation of ‘older’ less viable mitochondrial proteins in myoblasts from individuals affected by FSHD. Our results highlight the importance of post-transcriptional processes and protein turnover in FSHD pathology and provide a resource for the FSHD research community to explore this burgeoning aspect of FSHD.
2023-06-27 | PXD038818 | Pride
Project description:Facioscapulohumeral dystrophy (FSHD) is a neuromuscular disease characterized by progressive asymmetric muscle weakness. Myoblasts isolated from FSHD muscles exhibit morphological differentiation defects and show a distinct transcription profile. These abnormalities may be linked to the muscle weakness in FSHD patients. Here, we have tested whether fusion of FSHD myoblasts (obtained from 2 patients) with primary myoblasts isolated from 2 healthy individuals could correct the differentiation defects. Our results show that the number of hybrid myotubes with normal phenotype increased with the percentage of normal myoblasts initially cultured. We demonstrated that a minimum of 50% of normal nuclei is required for a phenotypic correction of the FSHD phenotype. To test the correction on the functional level we analyzed transcriptomic profiles of phenotypically corrected hybrid myotubes. These myotubes were cultured in DMEM with 10% FBS. The present study concerns gene expression of FSHD, normal and hybrid myotubes after RNA extraction (TriPrep NucleoSpin ® kit) according to manufacturer’s instructions. Gene expression was performed in single color on Agilent 8x60K Human whole genome (design 039494) minimum in duplicates in each condition. Transcriptomic profiles of phenotypically corrected hybrid myotubes showed that the expression of deregulated genes in FSHD myotubes became almost normal. We thus propose that while phenotypical and functional correction of FSHD is feasible, it requires more than 50% of normal myoblasts, it creates limitations for cell therapy in the FSHD context.
2015-08-17 | E-MTAB-3658 | biostudies-arrayexpress
Project description:RNAseq of FSHD and control LCLs and primary myoblasts with corresponding in vitro differentiated myotubes
2020-06-30 | GSE153523 | GEO
Project description:In human muscle, SMCHD1 mutations are associated with the onset of FSHD2, but the mechanism driving the disease onset remains unclear. A commonly accepted explanation is the loss of SMCHD1 binding to the D4Z4 locus activates the expression of DUX4 in FSHD2 muscle. In this study, we used human myoblasts having DUX4 non-permissive 4qB alleles as a model to study DUX4-independent functions of SMCHD1 on myoblast cell growth. Surprisingly, depletion of SMCHD1 in these cells resulted in a cell proliferation defect. Despite the absence of DUX4 target genes’ activation, these cells showed a repression of PAX7 target genes (a hallmark of FSHD) and similar changes in expression profile compared to FSHD myoblasts. Interestingly, downregulation of cell proliferation-related genes and dysregulation of fibroblasts-specific genes were observed in SMCHD1 knockdown myoblasts and FSHD2 myoblasts but not FSHD1 myoblasts. Additionally, we identified LAP2 as direct targets of SMCHD1. Depletion of LAP2 leads to cell proliferation defect similar to the effect after SMCHD1 knockdown. These data imply that DUX4 is not the only driver for the onset of FSHD, and SMCHD1 has DUX4-independent functions in muscle growth and development.
2024-06-25 | GSE190829 | GEO
Project description:In human muscle, SMCHD1 mutations are associated with the onset of FSHD2, but the mechanism driving the disease onset remains unclear. A commonly accepted explanation is the loss of SMCHD1 binding to the D4Z4 locus activates the expression of DUX4 in FSHD2 muscle. In this study, we used human myoblasts having DUX4 non-permissive 4qB alleles as a model to study DUX4-independent functions of SMCHD1 on myoblast cell growth. Surprisingly, depletion of SMCHD1 in these cells resulted in a cell proliferation defect. Despite the absence of DUX4 target genes’ activation, these cells showed a repression of PAX7 target genes (a hallmark of FSHD) and similar changes in expression profile compared to FSHD myoblasts. Interestingly, downregulation of cell proliferation-related genes and dysregulation of fibroblasts-specific genes were observed in SMCHD1 knockdown myoblasts and FSHD2 myoblasts but not FSHD1 myoblasts. Additionally, we identified LAP2 as direct targets of SMCHD1. Depletion of LAP2 leads to cell proliferation defect similar to the effect after SMCHD1 knockdown. These data imply that DUX4 is not the only driver for the onset of FSHD, and SMCHD1 has DUX4-independent functions in muscle growth and development.
2024-06-25 | GSE190828 | GEO
Project description:Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable skeletal myopathy. Clinical trials for FSHD are hindered by heterogeneous biomarkers poorly associated with clinical severity, requiring invasive muscle biopsy. Macroscopically FSHD presents with slow fatty replacement of muscle, rapidly accelerated by inflammation. Mis-expression of the transcription factor DUX4 is currently accepted to underlie FSHD pathogenesis and mechanisms including PAX7 target gene repression have been proposed.
Here we perform RNA-sequencing on MRI guided inflamed (n=24) and isogenic non-inflamed (n=24) muscle biopsies from the same clinically characterised FSHD patients, alongside isogenic peripheral blood mononucleated cells from a subset of patients (n=13), and unaffected controls. We employ multivariate models to evaluate the clinical associations of 5 published FSHD transcriptomic biomarkers.
We demonstrate that PAX7 target gene repression can discriminate control, inflamed and non-inflamed FSHD muscle independently of age and sex (p<0.013), while the discriminatory power of DUX4 target genes is limited to distinguishing FSHD muscle from control. Importantly, the level of PAX7 target gene repression in non-inflamed muscle associates with clinical assessments of FSHD severity (p=0.04). DUX4 target gene biomarkers in FSHD muscle show associations with lower limb fat fraction and D4Z4 array length, but not clinical assessment. Lastly, PAX7 target gene repression in FSHD muscle correlates with the level in isogenic peripheral blood mononucleated cells (p=0.002). A refined PAX7 target gene biomarker comprising 143/601 PAX7 target genes computed in peripheral blood (the FSHD muscle-blood biomarker) associates with clinical severity in FSHD patients (p<0.036). Our new circulating biomarker validates as a classifier of clinical severity in an independent data set of 54 FSHD patient blood samples, with improved power in older patients (p=0.03).
In summary, we present the minimally invasive FSHD muscle-blood biomarker of FSHD clinical severity valid in patient muscle and blood, with potential utility in routine disease monitoring and clinical trials.
| EGAS00001007350 | EGA
Project description:The specific gene(s) responsible for FSHD phenotype have not yet been identified. We used the Human GeneChip Exon 1.0 ST platform to analyze the global gene expression profiles of FSHD-1, FSHD-2 and controls during myogenic differentiation. In this dataset, we include the expression data of human primary myoblasts obtained from three FSHD-1 and two FSHD-2 patients, and three healthy controls (CN). This data are used to evaluate the molecular perturbation of FSHD upon muscle differentiation; we compared patients and CN proliferating myoblasts as well as the corresponding myotubes obtained after 8 days of cell differentiation. 16 expression profiles were generated from 6 different cell types: including myoblasts and myotubes from healthy donors and FSHD-1 and FSHD-2 patients. Gene probesets with P < 0.01 and FC > 2 were selected in FSHD-1 assay, whereas P < 0.001 and FC > 2 were used in FSHD-2, in the attempt to overcame problems due to the small sample size analyzed.
2011-07-07 | E-GEOD-26061 | biostudies-arrayexpress