Similar Datasets
Project description:Lamin A is a component of the inner nuclear membrane that, together with epigenetic factors, organizes the genome in higher order structures required for transcriptional control. Mutations in the lamin A/C gene cause several diseases belonging to the class of laminopathies, including muscular dystrophies. Nevertheless, molecular mechanisms involved in the pathogenesis of lamin A-dependent dystrophies are still largely unknown. The polycomb group (PcG) of proteins are epigenetic repressors and lamin A interactors, primarily involved in the maintenance of cell identity. Using a murine model of Emery-Dreifuss muscular dystrophy (EDMD), we show here that lamin A loss deregulated PcG positioning in muscle satellite stem cells, leading to derepression of non-muscle-specific genes and p16INK4a, a senescence driver encoded in the Cdkn2a locus. This aberrant transcriptional program caused impairment in self-renewal, loss of cell identity, and premature exhaustion of the quiescent satellite cell pool. Genetic ablation of the Cdkn2a locus restored muscle stem cell properties in lamin A/C-null dystrophic mice. Our findings establish a direct link between lamin A and PcG epigenetic silencing and indicate that lamin A-dependent muscular dystrophy can be ascribed to intrinsic epigenetic dysfunctions of muscle stem cells.
| S-EPMC7190994 | biostudies-literature
Project description:Polycomb group of proteins (PcG) and the nuclear Lamin A are key factors in the maintenance of chromatin higher order structures required for preserving cell identity. Mutations in the Lamin A/C gene cause several diseases, belonging to the class of laminopathies, including Emery-Dreifuss Muscular Dystrophy. Nevertheless, epigenetic mechanisms involved in the pathogenesis of lamin-dependent dystrophy are still largely unknown. We show that Lamin A loss causes deregulated PcG positioning in muscular stem cells followed by upregulation of adipogenic markers and induction of the senescence’s driver p16INK4a from Cdkn2a locus. This aberrant transcriptional programme causes impairment in self-renewal, loss of cell identity and premature exhaustion of quiescent satellite cell pool. Genetic ablation of Cdkn2a locus restores muscle growth and muscle stem cell properties in Lamin A/C null dystrophic mice. In conclusion, our findings suggest that Lamin A has an essential role in preserving satellite cell self-renewal capacity and indicate that Lamin A-dependent muscular dystrophy can be ascribed to intrinsic epigenetic dysfunctions of muscle stem cells
2020-02-04 | GSE123724 | GEO
Project description:Polycomb group of proteins (PcG) and the nuclear Lamin A are key factors in the maintenance of chromatin higher order structures required for preserving cell identity. Mutations in the Lamin A/C gene cause several diseases, belonging to the class of laminopathies, including Emery-Dreifuss Muscular Dystrophy. Nevertheless, epigenetic mechanisms involved in the pathogenesis of lamin-dependent dystrophy are still largely unknown. We show that Lamin A loss causes deregulated PcG positioning in muscular stem cells followed by upregulation of adipogenic markers and induction of the senescence’s driver p16INK4a from Cdkn2a locus. This aberrant transcriptional programme causes impairment in self-renewal, loss of cell identity and premature exhaustion of quiescent satellite cell pool. Genetic ablation of Cdkn2a locus restores muscle growth and muscle stem cell properties in Lamin A/C null dystrophic mice. In conclusion, our findings suggest that Lamin A has an essential role in preserving satellite cell self-renewal capacity and indicate that Lamin A-dependent muscular dystrophy can be ascribed to intrinsic epigenetic dysfunctions of muscle stem cells
2020-02-04 | GSE123723 | GEO
Project description:Polycomb dysfunctional transcriptional repression in muscle stem cells contributes to lamin dependent muscular dystrophy
| PRJNA509642 | ENA
Project description:Polycomb dysfunctional transcriptional repression in muscle stem cells contributes to lamin dependent muscular dystrophy [RNA-seq]
| PRJNA509645 | ENA
Project description:Polycomb dysfunctional transcriptional repression in muscle stem cells contributes to lamin dependent muscular dystrophy [ChIP-seq]
| PRJNA509646 | ENA
Project description:Laminopathies are a clinically heterogeneous group of disorders caused by mutations in the LMNA gene, which encodes the nuclear envelope proteins lamins A and C. The most frequent diseases associated with LMNA mutations are characterized by skeletal and cardiac involvement, and include autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy type 1B, and LMNA-related congenital muscular dystrophy (LMNA-CMD). Although the exact pathophysiological mechanisms responsible for LMNA-CMD are not yet understood, severe contracture and muscle atrophy suggest that mutations may impair skeletal muscle growth. Using human muscle stem cells (MuSCs) carrying LMNA-CMD mutations, we observe impaired myogenic fusion with disorganized cadherin/? catenin adhesion complexes. We show that skeletal muscle from Lmna-CMD mice is unable to hypertrophy in response to functional overload, due to defective fusion of activated MuSCs, defective protein synthesis and defective remodeling of the neuromuscular junction. Moreover, stretched myotubes and overloaded muscle fibers with LMNA-CMD mutations display aberrant mechanical regulation of the yes-associated protein (YAP). We also observe defects in MuSC activation and YAP signaling in muscle biopsies from LMNA-CMD patients. These phenotypes are not recapitulated in closely related but less severe EDMD models. In conclusion, combining studies in vitro, in vivo, and patient samples, we find that LMNA-CMD mutations interfere with mechanosignaling pathways in skeletal muscle, implicating A-type lamins in the regulation of skeletal muscle growth.
| S-EPMC7795708 | biostudies-literature
Project description:Disruption of the dystrophin complex causes muscle injury, dysfunction, cell death and fibrosis. Excess transforming growth factor (TGF) β signaling has been described in human muscular dystrophy and animal models, where it is thought to relate to the progressive fibrosis that characterizes dystrophic muscle. We now found that canonical TGFβ signaling acutely increases when dystrophic muscle is stimulated to contract. Muscle lacking the dystrophin-associated protein γ-sarcoglycan (Sgcg null) was subjected to a lengthening protocol to produce maximal muscle injury, which produced rapid accumulation of nuclear phosphorylated SMAD2/3. To test whether reducing SMAD signaling improves muscular dystrophy in mice, we introduced a heterozygous mutation of SMAD4 (S4) into Sgcg mice to reduce but not ablate SMAD4. Sgcg/S4 mice had improved body mass compared with Sgcg mice, which normally show a wasting phenotype similar to human muscular dystrophy patients. Sgcg/S4 mice had improved cardiac function as well as improved twitch and tetanic force in skeletal muscle. Functional enhancement in Sgcg/S4 muscle occurred without a reduction in fibrosis, suggesting that intracellular SMAD4 targets may be important. An assessment of genes differentially expressed in Sgcg muscle focused on those encoding calcium-handling proteins and responsive to TGFβ since this pathway is a target for mediating improvement in muscular dystrophy. These data demonstrate that excessive TGFβ signaling alters cardiac and muscle performance through the intracellular SMAD pathway.
| S-EPMC4303797 | biostudies-literature
Project description:Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by progressive weakness and degeneration of specific muscles. OPMD is due to extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Aggregation of the mutant protein in muscle nuclei is a hallmark of the disease. Previous transcriptomic analyses revealed the consistent deregulation of the ubiquitin-proteasome system (UPS) in OPMD animal models and patients, suggesting a role of this deregulation in OPMD pathogenesis. Subsequent studies proposed that UPS contribution to OPMD involved PABPN1 aggregation. Here, we use a Drosophila model of OPMD to address the functional importance of UPS deregulation in OPMD. Through genome-wide and targeted genetic screens we identify a large number of UPS components that are involved in OPMD. Half dosage of UPS genes reduces OPMD muscle defects suggesting a pathological increase of UPS activity in the disease. Quantification of proteasome activity confirms stronger activity in OPMD muscles, associated with degradation of myofibrillar proteins. Importantly, improvement of muscle structure and function in the presence of UPS mutants does not correlate with the levels of PABPN1 aggregation, but is linked to decreased degradation of muscle proteins. Oral treatment with the proteasome inhibitor MG132 is beneficial to the OPMD Drosophila model, improving muscle function although PABPN1 aggregation is enhanced. This functional study reveals the importance of increased UPS activity that underlies muscle atrophy in OPMD. It also provides a proof-of-concept that inhibitors of proteasome activity might be an attractive pharmacological approach for OPMD.
| S-EPMC8791501 | biostudies-literature
Project description:Limb-girdle muscular dystrophy type 2O (LGMD2O) belongs to a group of rare muscular dystrophies named dystroglycanopathies, which are characterized molecularly by hypoglycosylation of ?-dystroglycan (?-DG). Here, we describe the first dystroglycanopathy patient carrying an alteration in the promoter region of the POMGNT1 gene (protein O-mannose ?-1,2-N-acetylglucosaminyltransferase 1), which involves a homozygous 9-bp duplication (-83_-75dup). Analysis of the downstream effects of this mutation revealed a decrease in the expression of POMGNT1 mRNA and protein because of negative regulation of the POMGNT1 promoter by the transcription factor ZNF202 (zinc-finger protein 202). By functional analysis of various luciferase constructs, we localized a proximal POMGNT1 promoter and we found a 75% decrease in luciferase activity in the mutant construct when compared with the wild type. Electrophoretic mobility shift assay (EMSA) revealed binding sites for the Sp1, Ets1 and GATA transcription factors. Surprisingly, the mutation generated an additional ZNF202 binding site and this transcriptional repressor bound strongly to the mutant promoter while failing to recognize the wild-type promoter. Although the genetic causes of dystroglycanopathies are highly variable, they account for only 50% of the cases described. Our results emphasize the importance of extending the mutational screening outside the gene-coding region in dystroglycanopathy patients of unknown aetiology, because mutations in noncoding regions may be the cause of disease. Our findings also underline the requirement to perform functional studies that may assist the interpretation of the pathogenic potential of promoter alterations.
| S-EPMC3421125 | biostudies-literature