Exchange of subtelomeric regions between chromosomes 4q and 10q: a novel way to revert the FSHD genotype and phenotype
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1069681 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27744562_1.fastq.gz | Fastqsanger.gz | |||
| SRR27744562_2.fastq.gz | Fastqsanger.gz | |||
| SRR27744563_1.fastq.gz | Fastqsanger.gz | |||
| SRR27744563_2.fastq.gz | Fastqsanger.gz | |||
| SRR27744564_1.fastq.gz | Fastqsanger.gz |
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Project description:In this study we used the CRISPR-Cas9 technique to induce the targeted 4q35;10q26 translocation in FSHD myoblasts. We were able to demonstrate that t(4;10)(q35;q26) can generate recombinant genotypes which revert the pathological phenotype of the FSHD cells.
2024-03-01 | GSE254310 | GEO
Project description:Exchange of subtelomeric regions between chromosomes 4q and 10q: a novel way to revert the FSHD genotype.
| PRJEB61799 | ENA
Project description:Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder linked to contractions of the D4Z4 repeat array in the subtelomeric region of chromosome 4q. By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, we intend to identify disease-specific changes which are more likely to be involved in the early stages of the disease progression. The data will help to identify pathological mechanisms involved in FSHD. Keywords: Differentiation design
2007-10-23 | GSE9397 | GEO
Project description:Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder linked to contractions of the D4Z4 repeat array in the subtelomeric region of chromosome 4q. By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, we intend to identify disease-specific changes which are more likely to be involved in the early stages of the disease progression. The data will help to identify pathological mechanisms involved in FSHD. Experiment Overall Design: Comparison of the profiles of FSHD to 13 other conditions for disease-specific changes. The 13 conditions are NHM (Normal healthy muscle) n=15; JDM (Juvenile dermatomyositis) n=25; HSP (Human spastic paraplegia) n=4; FSHD (facioscapulohumeral dystrophy) unaffected n=5, affected n=9; FKRP (Fukutin related protein deficiency) n=7; ED-L (Emery-Dreifuss muscular dystrophy, lamin A/C deficiency) n=4; ED-E (Emery-Dreifuss muscular dystrophy, emerin deficiency) n=4; DYSF (dysferlinopathy) n=10; DMD (Duchenne Muscular Dystrophy) n=10; CALP (Calpain-3 deficiency) n=10; BMD (Becker Muscular Dystrophy) n=5; AQM (Acute quadriplegic myopathy) n=5; ALS (Amyotrophic lateral sclerosis) n=9.
2008-06-16 | E-GEOD-9397 | biostudies-arrayexpress
Project description:Facioscapulohumeral dystrophy (FSHD) is caused by a deletion in a D4Z4 macrosatellite repeat array in the 4q subtelomere that leads to somatic de-repression of the transcription factor DUX4. It is not fully understood how array contractions cause de-repression, but they alter the local chromatin structure of D4Z4, resulting in loss of heterochromatic markers. In order to determine whether pathogenic contractions also alter the nuclear organization of the FSHD locus, we designed an allele-aware, high-throughput circular chromosome conformation capture assay (4C-seq) that distinguishes the two 4q copies of the locus from each other and from a paralogous locus in the 10q subtelomere. Using a short sequence length polymorphism (SSLP) four kilobasepairs from the array as âharacterized the genomic contacts made by the four copies of the FSHD locus in muscle cell nuclei. The SSLP contacts predominate on the same chromosome arm as the bait, decaying rapidly beyond 30-40 Mb. Contacts on other chromosomes were enriched near centromeres and CTCF sites. We also found that the FSHD locus normally contacts regions adjacent to the nuclear lamina and with low overall gene expression. However, we found that the deleted locus in FSHD cells makes more contacts with regions with comparatively lower lamina adjacency and higher overall gene expression than in control cells. Furthermore, association of D4Z4 with components of the nuclear lamina was reduced in FSHD cells relative to control cells. Our results suggest that altered nuclear organization at 4q35 may be one factor in the de-repression of DUX4 in FSHD. 5 primary cells (2 control, 1 FSHD1, 1 FSHD2, and 1 FSHD3) were used to generate 4C libraries in biological duplicate, for a total of 10 4C libraries
2013-08-31 | E-GEOD-40673 | biostudies-arrayexpress
Project description:Facioscapulohumeral dystrophy (FSHD) is caused by a deletion in a D4Z4 macrosatellite repeat array in the 4q subtelomere that leads to somatic de-repression of the transcription factor DUX4. It is not fully understood how array contractions cause de-repression, but they alter the local chromatin structure of D4Z4, resulting in loss of heterochromatic markers. In order to determine whether pathogenic contractions also alter the nuclear organization of the FSHD locus, we designed an allele-aware, high-throughput circular chromosome conformation capture assay (4C-seq) that distinguishes the two 4q copies of the locus from each other and from a paralogous locus in the 10q subtelomere. Using a short sequence length polymorphism (SSLP) four kilobasepairs from the array as âharacterized the genomic contacts made by the four copies of the FSHD locus in muscle cell nuclei. The SSLP contacts predominate on the same chromosome arm as the bait, decaying rapidly beyond 30-40 Mb. Contacts on other chromosomes were enriched near centromeres and CTCF sites. We also found that the FSHD locus normally contacts regions adjacent to the nuclear lamina and with low overall gene expression. However, we found that the deleted locus in FSHD cells makes more contacts with regions with comparatively lower lamina adjacency and higher overall gene expression than in control cells. Furthermore, association of D4Z4 with components of the nuclear lamina was reduced in FSHD cells relative to control cells. Our results suggest that altered nuclear organization at 4q35 may be one factor in the de-repression of DUX4 in FSHD.
2013-08-31 | GSE40673 | 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: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:Facioscapulohumeral dystrophy (FSHD) is caused by decreased epigenetic repression of the D4Z4 macrosatellite array and recent studies have shown that this results in the expression of low levels of the DUX4 mRNA in skeletal muscle. Several other mechanisms have been suggested for FSHD pathophysiology and it remains unknown whether DUX4 expression can account for most of the molecular changes seen in FSHD. Since DUX4 is a transcription factor, we used RNA-seq to measure gene expression in muscle cells transduced with DUX4, and in muscle cells and biopsies from control and FSHD individuals. We show that DUX4 target gene expression is the major molecular signature in FSHD muscle together with a gene expression signature consistent with an immune cell infiltration. In addition, one unaffected individual without a known FSHD-causing mutation showed expression of DUX4 target genes. This individual has a sibling with FSHD and also without a known FSHD-causing mutation, suggesting the presence of yet unidentified modifier locus for DUX4 expression and FSHD. These findings demonstrate that expression of DUX4 accounts for the majority of the gene expression changes in FSHD skeletal muscle together with an immune cell infiltration. RNA-seq for muscle cells and biopsies from control and FSHD individuals.
2014-07-03 | E-GEOD-56787 | biostudies-arrayexpress
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