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Analysis of splicing abnormalities in the white matter of myotonic dystrophy type 1 brain using RNA-sequence

ABSTRACT: Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by the genomic expansions of CTG repeats, in which RNA-binding proteins, such as muscleblind-like protein, are sequestered in the nucleus, and abnormal splicing is observed in various genes. Although abnormal splicing reportedly occurs in the brains of patients with DM1, it is relation to the central nervous system symptoms is unknown. Several imaging studies have indicated substantial white matter (WM) defects in patients with DM1. Here, we performed RNA-sequencing and analysis of CTG repeat lengths in the frontal lobe of patients with DM1, separating the grey matter (GM) and WM, to investigate the splicing abnormalities in the DM1 brain, especially in the WM. The results demonstrated the number of repeats in the GM tended to be increase, with several genes showing similar levels of splicing abnormalities in the GM and WM, suggesting that the WM defects in DM1 are not only caused by aberrant splicing of GM RNA but also of WM RNA, which could be attributed to abnormal splicing of glial cell RNAs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224437 | GEO | 2023/10/25

REPOSITORIES: GEO

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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.

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Gene expression of white and grey matter demyelinated areas and normal appearing matter from Multiple Sclerosis leukocortial lesions of human post-mortem tissue

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Characterization of the deregulation of the RNAs associated to the RISC complex in skeletal muscle of DM1 patients (RISC-IP small RNA)

Project description:DM1 (OMIM #160900) is a chronic, slowly progressing multisystemic disease, with symptoms that include loss of muscle strength, myotonia and excessive fatigue. DM1 is caused by a dynamic expansion of CTG repeats, ranging from 50 to several thousands, in the 3’ untranslated region of the DMPK gene. Characteristic molecular features of the disease have been associated with a toxic RNA gain of function of the CUG expansions. Expanded CUG repeats have been demonstrated to be toxic per se in several cell types and animal models disrupting gene transcription and pre-mRNA alternative splicing. Deep sequencing is here used to characterize the deregulation of the RNAs associated to the RISC complex in the skeletal muscle of DM1 patients.

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Characterization of the deregulation of the RNAs associated to the RISC complex in skeletal muscle of DM1 patients (RISC-IP long RNA)

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Characterization of the deregulation of the RNAs associated to the RISC complex in skeletal muscle of DM1 patients (Input small RNA)

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Transcriptome Alterations in Myotonic Dystrophy Frontal Cortex

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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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