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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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

ABSTRACT: 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.

ORGANISM(S): Drosophila melanogaster

SUBMITTER: Lucie Picchio

PROVIDER: E-MTAB-1469 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Novel Drosophila model of myotonic dystrophy type 1: phenotypic characterization and genome-wide view of altered gene expression.

Picchio Lucie L Plantie Emilie E Renaud Yoan Y Poovthumkadavil Preethi P Jagla Krzysztof K

Human molecular genetics 20130321 14

Myotonic dystrophy type 1 (DM1) is a multisystemic RNA-dominant disorder characterized by myotonia and muscle degeneration. In DM1 patients, the mutant DMPK transcripts containing expanded CUG repeats form nuclear foci and sequester the Muscleblind-like 1 splicing factor, resulting in mis-splicing of its targets. However, several pathological defects observed in DM1 and their link with disease progression remain poorly understood. In an attempt to fill this gap, we generated inducible transgenic ...[more]

PMID: 23525904

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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.

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Alternative splicing and gene expression in a mouse model of myotonic dystrophy

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.

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Alternative splicing and gene expression in a mouse model of myotonic dystrophy

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Preclinical characterization of antagomiR-218 as a potential treatment for Myotonic Dystrophy

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Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy

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Increased Muscleblind levels by chloroquine treatment improves myotonic dystrophy type 1 phenotypes in in vitro and in vivo models

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Project description:The symptoms of Myotonic Dystrophy Type 1 (DM1) are multi-systemic and life-threatening. The neuromuscular disorder is rooted in a non-coding CTG microsatellite expansion in the DMPK gene that is correctly transcribed and physically sequesters the MBNL family of proteins. The high-affinity binding occurring between the proteins and the repetitions disallows MBNL proteins from performing their post-transcriptional splicing regulation leading to downstream molecular effects directly related to disease symptoms such as myotonia and muscle weakness. In this study, we build off of previously demonstrated evidence showing that the silencing of miR-23b and miR-218 can increase MBNL1 and 2 protein in DM1 cells. Here we use blockmiR antisense technology to block the binding sites of these miRNAs in order to increase MBNL translation into protein without binding to the microRNAs in DM1 muscle cells. The blockmiRs show therapeutic effects with the rescue of mis-splicing, MBNL subcellular localization, and transcriptomic expression proving that this novel and highly specific strategy could be a potentially viable therapy in Vivo.

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Precise small molecule cleavage of a r(CUG) repeat expansion in a myotonic dystrophy mouse model

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.

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