RNA-seq from WT and HSALR (a Myotonic Dystrophy type 1 model) mice
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 4000
ORGANISM(S): Mus musculus
SUBMITTER:
PROVIDER: E-MTAB-10842 | biostudies-arrayexpress |
SECONDARY ACCESSION(S): ERP131183
REPOSITORIES: biostudies-arrayexpress
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Project description:This study examined the effects of antisense oligonucleotides (ASOs) on the muscle transcriptome in a transgenic mouse model of myotonic dystrophy. Two ASOs were tested in HSALR transgenic mice. Both of the ASOs targeted mRNA from a human skeletal actin (hACTA1) transgene. This transgene contains an expanded CTG repeat in the 3M-bM-^@M-^Y untranslated region (UTR) (Mankodi et al M-bM-^@M-^\Myotonic dystrophy in transgenic mice expressing an expanded CUG repeatM-bM-^@M-^] Science 2000; 289:1769-72). ASO 445235 targeted the hACTA1 transcript in the 3M-bM-^@M-^Y UTR, downstream from the expanded repeat. ASO 190401 targeted the hACTA1 transcript in the coding region. The HSALR mice received 4 weeks of biweekly subcutaneous injections of vehicle (saline), ASO 190401, or ASO 445236 (n = 4 per group), at a dose of 25 mg/kg per injection. Wild-type mice of the same strain background received saline injections (n = 4). One week after the final injection, quadriceps muscle was harvested for RNA analysis. Four conditions, four arrays per condition, to compare WT and HSALR trangenic mice without treatment (saline) and to examine the effect of two oligos (vs. saline) in the HSALR transgenic mice.
2012-06-27 | E-GEOD-38962 | biostudies-arrayexpress
Project description:In order to examine the changes in gene expression between normal and myotonic dystrophic animals, gene expression array studies were done with extensor digitorum longus (EDL) of transgenic HSALR line 20b mice using Affymetrix MOE430 2.0 microarrays. We used EDL muscle from transgenic HSALR line 20b mice, maintained as homozygotes in an FVB inbred background and wild-type FVB mice purchased from Taconic. Affymetrix gene expression arrays were performed on HSALR and wild type EDL muscle
2012-10-21 | E-GEOD-24920 | biostudies-arrayexpress
Project description:Distinct RNA-mediated impacts on alternative splicing and extracellular matrix gene expression in a mouse model of myotonic dystrophy. Myotonic dystrophy (DM1) is associated with expression of expanded CTG DNA repeats as RNA (CUGexp RNA). To test whether CUGexp RNA creates a global splicing defect, we compared skeletal muscle of two mouse DM1 models, one expressing a CTGexp transgene, and another homozygous for a defective Mbnl1 gene. Strong correlation in splicing changes for ~100 new Mbnl1-regulated exons indicates loss of Mbnl1 explains >80% of the splicing pathology due to CUGexp RNA. In contrast, only about half of mRNA level changes can be attributed to loss of Mbnl1, indicating CUGexp RNA has Mbnl1-independent effects, particularly on mRNAs for extracellular matrix (ECM) proteins. We propose that CUGexp RNA causes two separate effects: loss of Mbnl1 function, disrupting splicing, and loss of another function that disrupts ECM mRNA regulation, possibly mediated by MBNL2. These findings reveal unanticipated similarities between DM1 and other muscular dystrophies. MBNL1 knockout and HSALR mice on FVB background. To test whether CUGexp RNA creates a global splicing defect, we compared skeletal muscle of two mouse DM1 models, one expressing a CTGexp transgene, and another homozygous for a defective Mbnl1 gene. These samples were compared to the skeletal muscle of a wildtype mouse.
2010-01-23 | E-GEOD-17986 | biostudies-arrayexpress
Project description:In order to examine the changes in gene expression between normal and myotonic dystrophic animals, gene expression array studies were done with extensor digitorum longus (EDL) of transgenic HSALR line 20b mice using Affymetrix MOE430 2.0 microarrays. We used EDL muscle from transgenic HSALR line 20b mice, maintained as homozygotes in an FVB inbred background and wild-type FVB mice purchased from Taconic.
2012-10-21 | GSE24920 | GEO
Project description:Myotonic dystrophy type 1 (DM1) is a life-threatening and chronically debilitating neuromuscular disease caused by the expansion of a CTG trinucleotide repeat in the 3'UTR of the DMPK gene. The mutant RNA forms insoluble structures capable of sequestering RNA binding proteins of the Muscleblind-like (MBNL) family, which ultimately originates phenotypes. In this work we demonstrate that treatment with the anti-autophagic drug chloroquine in Drosophila and mouse (HSALR) models, and patient-derived myoblasts, was sufficient to upregulate MBNL1 and 2 proteins. Extra Muscleblind was functional at the molecular level and improved splicing events regulated by MBNLs in all disease models. In vivo, chloroquine rescued locomotion and average crossectional muscle area, and extended median survival of DM1 flies. In HSALR mice the drug recovered muscular strength and histopathology signs, and reduced myotonia grade. Taken together these results offer a novel means to replenish the critically low levels of MBNLs in DM1.
2019-11-22 | GSE128844 | GEO
Project description:Myotonic Dystrophy (DM1) is a rare neuromuscular disease caused by the expansion of unstable CTG repeats in a non-coding region of the DMPK gene. CUG expansions in mutant DMPK transcripts fold into hairpins that sequester MBNL1 proteins in ribonuclear foci, depletion of MBNL1 being a chief contribution to disease symptoms such as muscle weakness and atrophy, and myotonia. Thus, the upregulation of endogenous MBNL1 levels may compensate for the sequestration. We have demonstrated that antisense oligonucleotides against miR-218 boost expression of MBNL1 and rescue phenotypes in disease models. Here we provide a preclinical characterization of an antagomiR-218 molecule using the HSALR mouse model and patient-derived myoblasts. In HSALR, antagomiR-218 rescued molecular and functional phenotypes in a dose-dependent manner, showed a good toxicity profile, and lasted some 15 days after a single subcutaneous injection. In muscle tissue, the antagomiR rescued the normal subcellular distribution of Mbnl1 and did not alter the percentage of myonuclei containing CUG foci. In patient-derived cells, antagomiR-218 improved defective fusion and differentiation and rescued up to 34% of the gene expression alterations found in the transcriptome of patient myoblasts. Importantly, miR-218 was found upregulated in DM1 muscle biopsies, which makes this miRNA a relevant therapeutic target.
2021-01-31 | GSE158216 | GEO
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
Project description:Myotonic dystrophy type 1 (DM1) is an incurable neuromuscular disorder caused by an expanded CTG repeat that is transcribed into r(CUG)exp. The RNA repeat expansion sequesters regulatory proteins such as Muscleblind-like protein 1 (MBNL1), which causes pre-mRNA splicing defects. The disease-causing r(CUG)exp has been targeted by antisense oligonucleotides, CRISPR-based approaches, and RNA-targeting small molecules. Herein, we describe a designer small molecule, Cugamycin, that targets the structure of r(CUG)exp and cleaves it in cells and in vivo. Cugamycin selectively cleaves r(CUG)exp while leaving short repeats of r(CUG) untouched. In contrast, oligonucleotides that recognize r(CUG) sequence rather than structure cleave both long and short r(CUG)-containing transcripts. In the HSALR mouse model of DM1, Cugamycin selectively ablates r(CUG)exp in disease-affected muscle. Transcriptomic, histological, and phenotypic studies demonstrate that Cugamycin broadly and specifically relieves DM1-associated defects without detectable off-targets. Thus, small molecules that bind and cleave RNA may have utility as lead chemical probes and medicines.
2019-03-22 | GSE127809 | GEO
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
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