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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 .

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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.

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Distinct Pathological Signatures in Human Cellular Models of Myotonic Dystrophy Subtypes

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2019-11-15 | GSE137494 | GEO

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2023-05-05 | GSE208360 | GEO

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

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2023-05-02 | PXD024107 | Pride

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