Signaling through the dystrophin glycoprotein complex affects the stress-dependent transcriptome in Drosophila
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ABSTRACT:
PROVIDER: PRJNA926602 | ENA |
REPOSITORIES: ENA
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Project description:Deficiencies in the human dystrophin glycoprotein complex (DGC), which links the extracellular matrix with the intracellular cytoskeleton, cause muscular dystrophies, a group of incurable disorders associated with heterogeneous muscle, brain and eye abnormalities. Stresses such as nutrient deprivation and aging cause muscle wasting, which can be exacerbated by reduced levels of the DGC in membranes, the integrity of which is vital for muscle health and function. Moreover, the DGC operates in multiple signaling pathways, demonstrating an important function in gene expression regulation. To advance disease diagnostics and treatment strategies, we strive to understand the genetic pathways that are perturbed by DGC mutations. Here, we utilize a Drosophila model to investigate the transcriptomic changes in mutants of four DGC components under temperature and metabolic stress. We identify DGC-dependent genes, stress-dependent genes and genes dependent on the DGC for a proper stress response, confirming a novel function of the DGC in stress-response signaling. This perspective yields new insights into the etiology of muscular dystrophy symptoms, possible treatment directions and a better understanding of DGC signaling and regulation under normal and stress conditions.
2023-01-31 | GSE223505 | GEO
Project description:Dysfunction of the dystrophin-glycoprotein complex (DGC) is a frequent cause of hereditary forms of muscular dystrophy. Although DGC function in maintaining skeletal muscle integrity has been well characterized, little is known about how the DGC complex is coordinately regulated at the transcriptional level. To test this hypothesis, we engineered HDAC4 stably overexpressing and control myotubes in an in vitro model of muscle differentiation. Here we present evidence that HDAC4, a neural activity-responsive histone deacetylase, is a critical transcriptional regulator of the DGC complex. We show that HDAC4 can repress multiple components of the DGC complex, including dystrophin and sarcoglycan family members in both cultured myotubes. To confirm this finding, the protein levels of core DGC complex members including dystrophin, sarcoglycan complex members, and additional dystrophin-associated proteins were evaluated in differentiated myotubes by western analysis. C2C12 mouse myotubes were infected with either a HDAC4 expressing or control (Neo) retroviruses. After stable selection, myotubes were differentiated at 90% confluency in 2% horse serum (Hyclone) for 4 days. At this time point, RNA was extracted and the two types of cells compared in a microarray analysis.
2010-05-25 | E-GEOD-10678 | biostudies-arrayexpress
Project description:Dysfunction of the dystrophin-glycoprotein complex (DGC) is a frequent cause of hereditary forms of muscular dystrophy. Although DGC function in maintaining skeletal muscle integrity has been well characterized, little is known about how the DGC complex is coordinately regulated at the transcriptional level. To test this hypothesis, we engineered HDAC4 stably overexpressing and control myotubes in an in vitro model of muscle differentiation. Here we present evidence that HDAC4, a neural activity-responsive histone deacetylase, is a critical transcriptional regulator of the DGC complex. We show that HDAC4 can repress multiple components of the DGC complex, including dystrophin and sarcoglycan family members in both cultured myotubes. To confirm this finding, the protein levels of core DGC complex members including dystrophin, sarcoglycan complex members, and additional dystrophin-associated proteins were evaluated in differentiated myotubes by western analysis. Keywords: genetic modification and cell type comparison of muscle cells
2008-03-25 | GSE10678 | GEO
Project description:Signaling through the insulin receptor governs central physiological functions related to cell growth and metabolism. Here we show by tandem native protein complex purification approach and super-resolution STED microscopy that insulin receptor activity requires association with the fundamental structural module in muscle, the dystrophin glycoprotein complex (DGC), and the desmosomal component plakoglobin (g-catenin). The integrity of this high-molecular-mass assembly renders skeletal muscle susceptibility to insulin because DGC-insulin receptor dissociation by plakoglobin downregulation reduced insulin signaling and caused atrophy. Furthermore, low insulin receptor activity in muscles from transgenic or fasted mice decreased plakoglobin-DGC-insulin receptor content on the plasma membrane, but not when plakoglobin was overexpressed. By masking b-dystroglycan LIR domains, plakoglobin prevents autophagic clearance of plakoglobin-DGC-insulin receptor co-assemblies and maintains their function. Our findings establish DGC as a signaling hub, and provide a possible mechanism for the insulin resistance in Duchenne Muscular Dystrophy, and for the cardiomyopathies seen with plakoglobin mutations.
2020-03-19 | PXD016989 | Pride
Project description:Goal was to assess protein linkers between microtubules and dystrophin (specifically dystrophin regions R4-15 and R20-23). Two paired 10-plex TMT experiments were used to compare sixteen unique Dystrophin Glycoprotein Complex (or microtubule) enrichments (four genotypes, each with n=4) plus four pooled samples to allow comparison across the two individual 10-plex experiments for microtubules or DGC. A pair of 10-plex TMT(20 tags total) for the DGC enrichements, and a second pair of TMT (20 tags) for the MT enrichments. Samples are gastroc skeletal muscle from mouse.
2020-09-21 | PXD021088 | Pride
Project description:To investigate how dystrophin deficiency affects phenotype of vascular smooth muscle cells
2024-05-31 | GSE232219 | GEO
Project description:Duchenne muscular dystrophy (DMD) is the most common fatal genetic disease. Clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing is a promising strategy for permanently curing DMD. In this study we developed a novel strategy for reframing DMD mutations by CRISPR-mediated large-scale excision of exons 46–54. We compared this approach to other DMD rescue strategies using DMD patient-derived primary muscle-derived stem cells (MDSCs) and found that it showed the highest efficiency in terms of restoring of dystrophin protein expression. We also confirmed that CRISPR from Prevotella and Francisella 1(Cpf1)-mediated genome editing could correct DMD mutation with higher specificity than CRISPR-associated protein 9 (Cas9). Furthermore, A patient-derived xenograft (PDX) DMD mouse model was established by transplanting DMD-MDSCs into immunodeficient mice. CRISPR gene editing components were intramuscularly delivered into the mouse model by adeno-associated virus vectors. Dystrophin expression levels were increased by 10%–30% in human DMD muscle fibers. The restored dystrophin in vivo was functional, as demonstrated by the expression of the dystrophin glycoprotein complex member β-dystroglycan. This study provides a sensitive indicator for in vivo efficacy of gene editing and lays the foundation for a clinical trial of DMD treatment with gene editing technology.
2021-02-28 | GSE167586 | GEO
Project description:Duchenne muscular dystrophy (DMD) is the most common fatal genetic disease. Clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing is a promising strategy for permanently curing DMD. In this study we developed a novel strategy for reframing DMD mutations by CRISPR-mediated large-scale excision of exons 46–54. We compared this approach to other DMD rescue strategies using DMD patient-derived primary muscle-derived stem cells (MDSCs) and found that it showed the highest efficiency in terms of restoring of dystrophin protein expression. We also confirmed that CRISPR from Prevotella and Francisella 1(Cpf1)-mediated genome editing could correct DMD mutation with higher specificity than CRISPR-associated protein 9 (Cas9). Furthermore, A patient-derived xenograft (PDX) DMD mouse model was established by transplanting DMD-MDSCs into immunodeficient mice. CRISPR gene editing components were intramuscularly delivered into the mouse model by adeno-associated virus vectors. Dystrophin expression levels were increased by 10%–30% in human DMD muscle fibers. The restored dystrophin in vivo was functional, as demonstrated by the expression of the dystrophin glycoprotein complex member β-dystroglycan. This study provides a sensitive indicator for in vivo efficacy of gene editing and lays the foundation for a clinical trial of DMD treatment with gene editing technology.
2021-02-28 | GSE167585 | GEO
Project description:Duchenne muscular dystrophy (DMD) is the most common fatal genetic disease. Clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing is a promising strategy for permanently curing DMD. In this study we developed a novel strategy for reframing DMD mutations by CRISPR-mediated large-scale excision of exons 46–54. We compared this approach to other DMD rescue strategies using DMD patient-derived primary muscle-derived stem cells (MDSCs) and found that it showed the highest efficiency in terms of restoring of dystrophin protein expression. We also confirmed that CRISPR from Prevotella and Francisella 1(Cpf1)-mediated genome editing could correct DMD mutation with higher specificity than CRISPR-associated protein 9 (Cas9). Furthermore, A patient-derived xenograft (PDX) DMD mouse model was established by transplanting DMD-MDSCs into immunodeficient mice. CRISPR gene editing components were intramuscularly delivered into the mouse model by adeno-associated virus vectors. Dystrophin expression levels were increased by 10%–30% in human DMD muscle fibers. The restored dystrophin in vivo was functional, as demonstrated by the expression of the dystrophin glycoprotein complex member β-dystroglycan. This study provides a sensitive indicator for in vivo efficacy of gene editing and lays the foundation for a clinical trial of DMD treatment with gene editing technology.
2021-02-28 | GSE167584 | GEO
Project description:Duchenne muscular dystrophy (DMD) is the most common fatal genetic disease. Clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing is a promising strategy for permanently curing DMD. In this study we developed a novel strategy for reframing DMD mutations by CRISPR-mediated large-scale excision of exons 46–54. We compared this approach to other DMD rescue strategies using DMD patient-derived primary muscle-derived stem cells (MDSCs) and found that it showed the highest efficiency in terms of restoring of dystrophin protein expression. We also confirmed that CRISPR from Prevotella and Francisella 1(Cpf1)-mediated genome editing could correct DMD mutation with higher specificity than CRISPR-associated protein 9 (Cas9). Furthermore, A patient-derived xenograft (PDX) DMD mouse model was established by transplanting DMD-MDSCs into immunodeficient mice. CRISPR gene editing components were intramuscularly delivered into the mouse model by adeno-associated virus vectors. Dystrophin expression levels were increased by 10%–30% in human DMD muscle fibers. The restored dystrophin in vivo was functional, as demonstrated by the expression of the dystrophin glycoprotein complex member β-dystroglycan. This study provides a sensitive indicator for in vivo efficacy of gene editing and lays the foundation for a clinical trial of DMD treatment with gene editing technology.
2021-02-28 | GSE167583 | GEO