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Histone deacetylase 4 represses dystrophin-glycoprotein (DGC) complex expression

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE10678 | GEO | 2008/03/25

SECONDARY ACCESSION(S): PRJNA107661

REPOSITORIES: GEO

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Histone deacetylase 4 represses dystrophin-glycoprotein (DGC) complex expression

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

Signaling through the dystrophin glycoprotein complex affects the stress-dependent transcriptome in Drosophila

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

A signaling hub of insulin receptor dystrophin glycoprotein complex and plakoglobin regulates muscle size

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

Dystrophin domains R4-15 and R20-23

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

Protein Identification and Post-translational Analysis of DMD and its associated Proteins in H19-proficient and -deficient Cells

Project description:Dystrophin proteomic regulation in Muscular Dystrophies (MD) remains unclear. We report that a long noncoding RNA (lncRNA) H19 associates with dystrophin. To investigate the biological roles of this interaction in vivo, we performed mass spectrometry analysis of dystrophin and its associated proteins in H19-proficient and -deficient C2C12 myotubes. Mass spectrometry data indicated that in H19-proficient myotubes, dystrophin associates with components of dystrophin-associated protein complex (DPC); however, in H19-deficient myotubes, dystrophin associated with UBA1, UB2G1, TRIM63 ubiquitin E3 ligase and ubiquitin. In H19-deficient myotubes, dystrophin was post-translationally modified with K48-linked poly-ubiquitination at Lys3577 (referred to as Ub-DMD). This mass spectrometry study demonstrated that lncRNA H19, associates with dystrophin and inhibits E3 ligase-dependent Ub-DMD formation and its subsequent proteasomal degradation. Based on this study, H19 RNA oligonucleotides conjugated with a muscle homing ligand Agrin (referred to as AGR-H19) and Nifenazone, a TRIM63-specific small molecule inhibitor, reverses the dystrophin degradation in iPSC-derived skeletal muscle cells from Becker Muscular Dystrophy patients. Furthermore,treatment of mdx mice with exon-skipping reagent, in combination with either AGR-H19 or Nifenazone, dramatically stablized dystrophin, preserved skeletal/cardiac muscle histology, and improved strength/heart function. In summary, this mass spectrometry study paves the way to meaningful targeted therapeutics for BMD and certain DMD patients.

2020-08-19 | PXD020566 | Pride

Mouse Models for Muscular Dystrophy

Project description:Comparative analysis of gene expression levels from hindlimb muscle tissue from 8 week old mouse models for muscular dystrophy. We have used mouse models with dystrophin-, sarcoglycan-, sarcospan-, or dysferlin-deficiency. Keywords = muscular dystrophy

2010-06-06 | E-GEOD-2112 | biostudies-arrayexpress

Mouse Models for Muscular Dystrophy

2005-11-24 | GSE2112 | GEO

Mus musculus

Project description:Histone deacetylase 4 represses dystrophin-glycoprotein (DGC) complex expression

| PRJNA107661 | ENA

Molecular signatures of membrane protein complexes underlying muscular dystrophy

Project description:Mutations in genes encoding components of the sarcolemmal dystrophin-glycoprotein complex (DGC) are responsible for a large number of muscular dystrophies. As such, molecular dissection of the DGC is expected to both reveal pathological mechanisms, and provides a biological framework for validating new DGC components. Establishment of the molecular composition of plasma-membrane protein complexes has been hampered by a lack of suitable biochemical approaches. Here we present an analytical workflow based upon the principles of protein correlation profiling that has enabled us to model the molecular composition of plasma-membrane protein complexes in mouse skeletal muscle. We also report our analysis of protein complexes in mice harboring mutations in DGC components, which implicates cell-adhesion pathways directly targeted by NFκB in the pathophysiology of DGC-related muscular dystrophies. Our study suggests that inflammatory and compensatory mechanisms are activated in these diseases. Additionally, it provides a molecular framework that will facilitate refinement of our understanding of the DGC, identification of protein biomarkers of neuromuscular disease, and pharmacological interrogation of the DGC in adult skeletal muscle.

2016-04-22 | PXD004020 | Pride

Molecular signatures of membrane protein complexes underlying muscular dystrophy

2020-03-12 | PXD002846 | Pride

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