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Modeling of myogenesis using human embryonic stem cells reveals myotonic dystrophy type 1 specific misregulated cellular processes

ABSTRACT: We report the analysis of RNA sequencing results performed on human embryonic stem cells, carrying the myotonic dystrophy type 1 (DM1) mutation naturally, and their derived myoblasts and myotubes. The goal of the study was to reveal DM1-specific mechanisms during early myogenic development. After RNAseq analysis we found a subtle aberrant inflammation response in DM1 myoblasts possibly leading to an abnormal myotube formation thereafter. In addition an increased CpG methylation pattern upstream of the DM1 mutation was found and RNA missplicing events start to be abundantly present from the myotube stage on. We conclude that our in vitro model can recapitulate DM1-specific mechanisms and opens doors to a deeper understanding of the fundamental mechanisms of humen disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160916 | GEO | 2022/03/31

REPOSITORIES: GEO

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Deregulation of alternative splicing by toxic CUG repeats in astrocytes from a mouse model of myotonic dystrophy

Project description:Myotonic dystrophy type 1 (DM1) is a severe multisystemic disorder mediated by toxic RNA and abnormal RNA processing. Although splicing defects can explain some key disease symptoms, important gaps exist in our understanding of brain pathology, impeding the rational development of therapies. Here we investigated the different impact of DM1 on astrocytes, using a transgenic mouse model that expresses DM1-associated toxic CUG repeats-containing RNA. RNA sequencing revealed critical missplicing in transcripts that regulate cell adhesion, cytoskeleton and morphogenesis specific to astrocytes. These defects correlated with functional abnormalities in the assembly of focal adhesions and migration in culture, as well as defective astrocyte ramification and reorientation in vivo. Our results demonstrate that DM1 is critically deleterious for the adhesion and morphogenesis of astrocytes, possibly compromising the support and regulation of synaptic function .

2021-04-02 | GSE162093 | GEO

Recovery in the intrinsic myogenic program of congenital myotonic dystrophy myoblasts after excision of the expanded (CTG)n repeat

Project description:The congenital form of myotonic dystrophy type 1 (cDM) is caused by large-scale expansion of a (CTG•CAG)n repeat in DMPK and DM1-AS. Production of toxic transcripts with long trinucleotide tracts from these genes results in impediment of myogenic differentiation capacity as cDM’s most prominent morpho-phenotypic hallmark. In the current in vitro study, we compared the early differentiation programs of isogenic cDM myoblasts with and without a (CTG)2600 repeat obtained by gene editing. We found that excision of the repeat restored the ability of cDM myoblasts to engage in myogenic fusion, preventing that the ensuing myotubes remained immature. Although the cDM-typical epigenetic status of the DM1 locus and the expression of genes therein were not altered upon removal of the repeat, analyses at the transcriptome and proteome level revealed that early abnormalities in the temporal expression of differentiation regulators, myogenic progression markers and alternative splicing patterns before and immediately after the onset of differentiation became normalized. Our observation that molecular and cellular features of cDM are reversible and can be corrected by repeat-directed genome editing in muscle progenitors is important information for future development of gene therapy for different forms of DM1.

2019-11-20 | PXD016056 | Pride

Distinct Pathological Signatures in Human Cellular Models of Myotonic Dystrophy Subtypes

Project description:Myotonic dystrophy (DM) is the most common autosomal dominant muscular dystrophy and encompasses both skeletal muscle and cardiac complications. Myotonic dystrophy is nucleotide repeat expansion disorder in which type 1 (DM1) is due to a trinucleotide repeat expansion on chromosome 19 and type 2 (DM2) arises from a tetranucleotide repeat expansion on chromosome 3. Developing representative models of myotonic dystrophy in animals has been challenging due to instability of nucleotide repeat expansions, especially for DM2 which is characterized by nucleotide repeat expansions often greater than 5000 copies. To investigate mechanisms of human DM, we generated cellular models of DM1 and DM2. We used regulated MyoD expression to reprogram urine-derived cells into myotubes. In this cell model, we found impaired dystrophin expression, MBNL foci, and aberrant splicing in DM1 but not in DM2 cells. We generated induced pluripotent stem cells (iPSC) from healthy controls, DM1 and DM2 subjects and differentiated these into cardiomyocytes. DM1 and DM2 cells displayed an increase in RNA foci concomitant with cellular differentiation. IPSC-derived cardiomyocytes from DM1 but not DM2 had aberrant splicing and MBNL sequestration. High resolution imaging revealed tight association between MBNL clusters and RNA FISH foci in DM1. Ca2+ transients differed between DM1 and DM2 IPSC-derived cardiomyocytes and from healthy control cells. RNA-sequencing from DM1 and DM2 iPSC-derived cardiomyocytes both altered gene expression as well as distinct splicing patterns as differential between DM1 and DM2. Together these data support that DM1 and DM2, despite some shared clinical and molecular features, have distinct pathological signatures.

2019-02-12 | GSE125638 | GEO

AntimiR blocking of miR-23b and -218 corrects myotonic dystrophy primary cell defects over a wide range of CTG repeat expansions.

Project description:This study tested candidate therapeutic antimiRs in a comprehensive new collection of primary myoblasts derived from myotonic dystrophy type 1 (DM1) patients. DM1 is caused by genetically unstable CTG repeat expansions in the DMPK gene and has multiple clinical presentations, likely because of variable repeat sizes at the tissue and organ levels. Expanded DMPK transcripts deplete Muscleblind-Like Splicing Regulator protein MBNL1, which in turn causes DM1 symptoms. A promising therapeutic approach increases the expression of MBNL1 by blocking natural repressors miR-23b and miR-218 employing antimiRs with chemical modifications designed for a better pharmacological profile in humans. In untreated primary cells, we demonstrate that upregulated therapeutic targets miR-23b and miR-218 and reduced MBNL1 protein levels inversely correlate with CTG repeat size, supporting that active MBNL1 protein repression synergizes with the sequestration by CUG repeats in DM1. Upon treatment with novel antimiRs, multiple readouts of RNA toxicity associated with typical DM1 alterations improved. MBNL1-dependent exon inclusions, and myoblast fusion and myotube area defects, showed robust correction over a wide range of CTG expansions. Unexpectedly, antimiR treatment also reduced DMPK transcript levels and the number of ribonuclear aggregates. Based on these data, we selected a leading antimiR for further transcriptomics characterization and demonstrated that it reversed up to 68% of dysregulated genes. The study revealed that the candidate antimiRs could provide therapy to clinically relevant DM1 forms over a wide range of repeat sizes and genetic backgrounds by simultaneously reducing MBNL1 sequestration and derepressing protein synthesis.

2024-05-01 | GSE237411 | GEO

Cell-type specific dysregulation of RNA alternative splicing in short tandem repeat mouse knockin models of myotonic dystrophy

Project description:Short tandem repeats (STRs) are prone to expansion mutations that cause multiple hereditary neurological and neuromuscular diseases. To study pathomechanisms using mouse models that recapitulate the tissue specificity and developmental timing of an STR expansion gene, we used rolling circle amplification and CRISPR/Cas9-mediated genome editing to generate Dmpk CTG expansion (CTGexp) knockin models of myotonic dystrophy type 1 (DM1). We demonstrate that skeletal muscle myoblasts and brain choroid plexus epithelial cells are particularly susceptible to Dmpk CTGexp mutations and RNA mis-splicing. Our results implicate dysregulation of muscle regeneration and cerebrospinal fluid homeostasis as early pathogenic events in DM1.

2019-11-15 | GSE137494 | GEO

Clearance of defective muscle stem cells by senolytics reduces the expression of senescence-associated secretory phenotype and restores myogenesis in myotonic dystrophy type 1

Project description:Muscle weakness and atrophy are clinical hallmarks of myotonic dystrophy type 1 (DM1). Muscle stem cells, which contribute to skeletal muscle growth and repair, are also affected in this disease. However, the molecular mechanisms leading to this defective activity and the impact on the disease severity are still elusive. Here, we explored through an unbiased approach the molecular signature leading to myogenic cell defects in DM1. Single cell RNAseq data revealed the presence of a specific subset of DM1 myogenic cells expressing a senescence signature, characterized by the high expression of genes related to senescence-associated secretory phenotype (SASP). This profile was confirmed using different senescence markers in vitro and in situ. Accumulation of intranuclear RNA foci in senescent cells, suggest that RNA-mediated toxicity contribute to senescence induction. High expression of IL-6, a prominent SASP cytokine, in the serum of DM1 patients was identified as a biomarker correlating with muscle weakness and functional capacity limitations. Drug screening revealed that the BCL-XL inhibitor (A1155463), a senolytic drug, can specifically target senescent DM1 myoblasts to induce their apoptosis and reduce their SASP. Removal of senescent cells re-established the myogenic function of the non-senescent DM1 myoblasts, which displayed improved proliferation and differentiation capacity in vitro; and enhanced engraftment following transplantation in vivo. Altogether this study presents a well-defined senescent molecular signature in DM1 untangling part of the pathological mechanisms observed in the disease; additionally, we demonstrate the therapeutic potential of targeting these defective cells with senolytics to restore myogenesis.

2023-05-05 | GSE208360 | GEO

RNA sequencing of skeletal muscle of myotonic dystrophic (DM1) patients

Project description:Introduction: Myotonic dystrophy of type 1 (DM1), the most common dystrophy in adults, is an autosomal dominant inherited disease, affecting around 1 in 8000 person. Patients suffering from DM1 develop essentially muscle disorders such as myotonia, muscle weakness, muscle loss and atrophy. The disease is caused by the mutation of the DMPK "Dystrophia Myotonica Protein Kinase" gene. The mutation correspond to an abnormally large expansion of CTG tri-nucleotides repeats located in the 3'-untranslated region of this gene. Expanded CTG repeats are normally transcribed, but accumulates in RNA aggregates that sequester RNA-binding proteins such as the splicing regulator MBNL1. Consequently, due to MBNL1 sequestration, DM1 is characterized by aberrant splicing of a wide number of mRNA, which are themselves responsible for the symptoms observed in the disease. Purpose: To determine as much as possible novel splicing misregulations taking place in DM1 skeletal muscle, we performed a paired-end RNA sequencing (RNA-seq) using muscles samples of normal individuals (CTRL, n=3) versus muscles of DM1 patients (DM1, n=3). The data was analyzed by a bioinformatical software, called MISO, in order to map the alternative splicing changes between normal and DM1 muscle. The aim of this study was to get a broad and precise view of the splicing changes occurring in DM1 muscle.

2017-08-24 | GSE85984 | GEO

Periostin as a blood biomarker of muscle cell fibrosis, cardiomyopathy and disease severity in myotonic dystrophy type 1

Project description:Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy and is caused by an repeat expansion [r(CUG)exp] located in the 3' untranslated region of the DMPK gene. Symptoms include skeletal and cardiac muscle dysfunction and fibrosis. In DM1, there is a lack of established biomarkers in routine clinical practice. Thus, we aimed to identify a blood biomarker with relevance for DM1-pathophysiology and clinical presentation.

2023-05-02 | PXD024107 | Pride

Dynamics and variability of transcriptomic dysregulation in congenital myotonic dystrophy during childhood development

Project description:Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy caused by expansion of a CTG repeat microsatellite within DMPK. In 10-20% of individuals with DM1, symptomatic onset begins at birth; these patients are classified as congenital myotonic dystrophy (CDM). While dysregulation of RNA metabolism, specifically alternative splicing, has been linked to disease pathology in adult-onset DM1, little is known about the mechanism of CDM. Biopsies from individuals (CDM), age range 0.04-16 years, were subjected to total RNA-seq to quantify the transcriptomic dysregulation throughout pediatric development. To achieve this, they were compared against age matched pediatric controls which revealed a triphasic pattern of dysregulation not before seen observed in CDM. CDM samples were also compared to adult-onset (DM1) individuals which showcased a shared disease signature to seen in all individuals with myotonic dystrophy irrespective of disease age of onset.

2022-11-17 | GSE201255 | GEO

RNA-targeting Cas9 corrects molecular and physiological features in pre-clinical model of myotonic dystrophy type 1

Project description:In this Study, we used RNA-targeting Cas9 (RCas9) to reverse characteristic Myotonic Dystrophy (DM1) cellular phenotypes such as elimination of RNA foci, MBNL relocalization, and reversal of transcriptome-wide splicing in a mouse model of myotonic Dystrophy (DM1). Furthermore we show that gene expression is not altered with RCas9 treatment in WT mice with or without treatment with immunosuppression

2020-07-01 | GSE152033 | GEO

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