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Effect of CWG-cPIP on alternative splicing defects in CUG mouse brain

ABSTRACT: CWG-cPIP targets CAG/CTG (CWG) triplet repeat DNA to inhibit the transcription in a repeat length-dependent manner. To investigate effects of CWG-cPIP on alternative splicing defects in the brain of CUG300 mice, which we developed as a model of DM1, CWG-cPIP (83 ug/kg) was injected into mouse hippocampus. RNA sequencing analysis was performed using mouse hippocampus 10 days later.

ORGANISM(S): Mus musculus

PROVIDER: GSE210837 | GEO | 2023/10/11

REPOSITORIES: GEO

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Effect of CWG-cPIP on transcriptome defects in CUG mouse brain

Project description:CWG-cPIP targets CAG/CTG (CWG) triplet repeat DNA to inhibit the transcription in a repeat length-dependent manner. To investigate effects of CWG-cPIP on transcriptome defects in the brain of CUG300 mice, which we developed as a model of DM1, CWG-cPIP (83 ug/kg) was injected into mouse hippocampus. RNA sequencing analysis was performed using mouse hippocampus 10 days later.

2023-10-11 | GSE210838 | GEO

Off-target effect of CWG-cPIP on gene expression of mouse hippocampus

Project description:CWG-cPIP targets CAG/CTG (CWG) triplet repeat DNA to inhibit the transcription in a repeat length-dependent manner. To investigate off-target effects of CWG-cPIP on gene expression in the brain, CWG-cPIP (83 ug/kg) was injected into mouse hippocampus. RNA sequencing analysis was performed using vehicle- or CWG-cPIP-injected mouse hippocampus 3 weeks later, mixing with ERCC RNA spike-in controls.

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Off-target effect of CWG-cPIP on gene expression of human fibroblasts

Project description:CWG-cPIP targets CAG/CTG (CWG) triplet repeat DNA to inhibit the transcription in a repeat length-dependent manner. To investigate off-target effects of CWG-cPIP on gene expression in cells, CWG-cPIP (1 μM) was treated to human fibroblasts. RNA sequencing analysis was performed using vehicle- or CWG-cPIP-treated human fibroblasts 7 days later, mixing with ERCC RNA spike-in controls.

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Off-target effect of CWG-cPIP on gene expression of mouse Striatum

Project description:CWG-cPIP targets CAG/CTG (CWG) triplet repeat DNA to inhibit the transcription in a repeat length-dependent manner. To investigate off-target effects of CWG-cPIP on gene expression in the brain, CWG-cPIP (664 ug/kg) was intracerebroventricularly injected into mouse. RNA sequencing analysis was performed using vehicle- or CWG-cPIP-injected mouse striatum 3 weeks later, mixing with ERCC RNA spike-in controls.

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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.

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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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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

Three-dimensional chromatin interactions remain stable upon CAG/CTG repeat expansion

Project description:Expanded CAG/CTG repeats underlie thirteen neurological disorders, including myotonic dystrophy type 1 (DM1) and Huntington’s disease (HD). Upon expansion, CAG/CTG repeat loci acquire heterochromatic characteristics. This observation raises the hypothesis that repeat expansion provokes changes to higher-order chromatin conformation and thereby affects both gene expression in cis and the genetic instability of the repeat tract. Here we tested this hypothesis directly by performing 4C sequencing at the DMPK and HTT loci from DM1 and HD patient-derived cells. Surprisingly, chromatin contacts remain unchanged upon repeat expansion at both loci. This was true for expanded alleles with different DNA methylation levels and CTCF binding. Repeat tract sizes ranging from 15 to 1,700 repeats displayed strikingly similar chromatin interaction profiles. Moreover, the ectopic insertion of an expanded CAG repeat tract did not change the three-dimensional chromatin conformation of the surrounding genomic region. Our findings argue that extensive changes in heterochromatic properties are not enough to alter chromatin conformation at expanded CAG/CTG repeat loci. We conclude that 3D chromatin conformation is unlikely to drive repeat expansions or changes in gene expression in expanded CAG/CTG repeat disorders. This SuperSeries is composed of the SubSeries listed below.

2020-04-07 | GSE148185 | GEO

4C-seq: Three-dimensional chromatin interactions of FMR1, HTT, DMPK, and GFP viewpoints.

2020-04-07 | GSE148176 | GEO

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