Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE137494 | GEO | 2019/11/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Comparative analysis of Mbl attenuation and CUG non-coding repeats expression in Drosophila larval muscles

Project description:Myotonic dystrophy type 1 (DM1) is a neuro-muscular disorder caused by CTG triplet expansion in the 3-UTR of the DMPK gene. Mutated transcripts aggregate in muscle nuclei and sequester the MBNL1 splicing factor. To assess the involvement of Mbl sequestration on transcriptpion deregulation in DM1, we performed genome wide analyses of gene expression of DM1 Drosophila model in three different genetic contexts: Mef>mblRNAi, Mef>600CTG, Mef>960CTG vs. Mef>lacZ control line.

2013-04-01 | E-MTAB-1469 | biostudies-arrayexpress

Comparative analysis of Bruno-3 gain of function in Drosophila larval muscles

Project description:Myotonic dystrophy type 1 (DM1) is a neuro-muscular disorder caused by CTG triplet expansion in the 3'-UTR of the DMPK gene. Mutated transcripts aggregate in muscle nuclei and increase CUGBP1 stability by a not-yet determined mechanism. To assess the involvement of CUGBP1 in DM1, we used Drosophila as a model of the disease and we performed genome wide analyses of gene expression of bru-3 (CUGBP1 orthologue) gain of function line (Mef>bru-3) vs. Mef>lacZ control line.

2017-03-24 | E-MTAB-3231 | biostudies-arrayexpress

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

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

2018-07-15 | GSE108591 | GEO

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

2018-07-15 | GSE108590 | GEO

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

2018-07-15 | GSE108589 | 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

Short tandem repeats susceptible to pathogenic instability linked to chromatin domain disruption

Project description:More than 25 inherited human disorders are caused by the unstable expansion of repetitive DNA sequences termed short tandem repeats (STRs). A fundamental unresolved question is why some STRs are susceptible to pathologic expansion, whereas thousands of repeat tracts across the human genome are relatively stable. Here, we discover that nearly all disease-associated STRs (daSTRs) are located at boundaries demarcating 3D chromatin domains. We identify a subset of boundaries with markedly higher CpG island density compared to the rest of the genome. daSTRs specifically localize to ultra-high-density CpG island boundaries, suggesting they might be hotspots for epigenetic misregulation or topological disruption upon STR expansion. Fragile X Syndrome (FXS) patients exhibit severe boundary disruption in a manner that correlates with local loss of CTCF occupancy and the degree of FMR1 silencing. Our data uncover higher-order chromatin architecture as a new dimension in understanding repeat expansion disorders.

2018-08-29 | GSE111170 | GEO

Bisulfite-seq: Analysis of CpG methylation at two CTCF binding sites flanking the CTG repeats of DMPK.

Project description:Bisulfite sequencing was performed on GM04604 (UN-B), GM06077 (DM1-A), and GM04648 (DM1-B) patient cells to determine the levels of CpG methylation present at two CTCF sites closely flanking the CTG repeats of DMPK.

2020-04-07 | GSE148177 | 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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data