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Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats

ABSTRACT: Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats

PROVIDER: PRJNA783310 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17029610_1.fastq.gz	Fastqsanger.gz
	SRR17029610_2.fastq.gz	Fastqsanger.gz
	SRR17029611_1.fastq.gz	Fastqsanger.gz
	SRR17029611_2.fastq.gz	Fastqsanger.gz
	SRR17029612_1.fastq.gz	Fastqsanger.gz

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Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats [mouse]

Project description:Myotonic dystrophy type 1 (DM1) is an RNA-dominant disease whose pathogenesis stems from the functional loss of muscleblind-like RNA-binding proteins (RBPs), which causes the formation of alternative-splicing defects. The loss of functional muscleblind-like protein 1 (MBNL1) results from its nuclear sequestration by mutant transcripts containing pathogenic expanded CUG repeats (CUGexp). Here we show that an MBNL1∆ RBP engineered to act as a decoy for CUGexp reverses the toxicity of the mutant transcripts.

2022-01-03 | GSE189515 | GEO

Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats [human]

2022-01-03 | GSE189503 | GEO

Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats [mouse]

Project description:Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats [mouse]

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Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats [human]

Project description:Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats [human]

| PRJNA783289 | ENA

Atrial and ventricular transcriptomic alterations in a cardiac mouse model of myotonic dystrophy expressing 960 CUG repeats

Project description:Purpose: The goal of this study was to characterize the atrial and ventricular transcriptomic changes in a cardiac mouse model of myotonic dystrophy. The mouse model utilizes a bitransgenic system for doxycycline (dox) inducible and cardiomyocyte specific expression of pathogenic RNA containing 960 CUG repeats. Bitransgenic animals (called CUG960 mice) homozygous for the TREDT960I transgene (containing 960 interrupted CTG repeats) and hemizygous for reverse transactivator (rtTA) transgene containing a cardiomyocyte-specific alpha myosin heavy chain promoter are given dox food for expression of CUG repeat RNA. Mice hemizygous for rtTA transgene (MHCrtTA) given dox food were used as controls. Methods:We performed RNA-seq for high-resolution analysis of transcriptomic alterations in atria and ventricles of CUG960 experimental and MHCrtTA control mice given dox chow since postnatal day 1 (PN1) for a period of 10 weeks. Results: We identified pathogenic CUG repeat RNA induced gene expression and alternative splicing changes in ion transport genes that are associated with inherited cardiac conduction diseases, including a subset of genes involved in calcium handling. Conclusions: We identified potential tissue-specific mechanisms contributing to the cardiac disease relevant phenotypes in an animal model of DM1.

2021-01-15 | GSE164825 | GEO

Deregulation of alternative splicing by toxic CUG repeats in astrocytes from a mouse model of myotonic dystrophy

Project description:Myotonic dystrophy type 1 (DM1) is a severe multisystemic disorder mediated by toxic RNA and abnormal RNA processing. Although splicing defects can explain some key disease symptoms, important gaps exist in our understanding of brain pathology, impeding the rational development of therapies. Here we investigated the different impact of DM1 on astrocytes, using a transgenic mouse model that expresses DM1-associated toxic CUG repeats-containing RNA. RNA sequencing revealed critical missplicing in transcripts that regulate cell adhesion, cytoskeleton and morphogenesis specific to astrocytes. These defects correlated with functional abnormalities in the assembly of focal adhesions and migration in culture, as well as defective astrocyte ramification and reorientation in vivo. Our results demonstrate that DM1 is critically deleterious for the adhesion and morphogenesis of astrocytes, possibly compromising the support and regulation of synaptic function .

2021-04-02 | GSE162093 | GEO

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.

2019-03-22 | GSE127809 | GEO

Atrial and ventricular transcriptomic alterations in a cardiac mouse model of myotonic dystrophy expressing 960 CUG repeats

Project description:Atrial and ventricular transcriptomic alterations in a cardiac mouse model of myotonic dystrophy expressing 960 CUG repeats

| PRJNA692163 | ENA

Deregulation of alternative splicing by toxic CUG repeats in astrocytes from a mouse model of myotonic dystrophy

Project description:Deregulation of alternative splicing by toxic CUG repeats in astrocytes from a mouse model of myotonic dystrophy

| PRJNA680559 | ENA

Expanded CUG repeat RNA alters gene expression profiles in myotonic dystrophy model cells

Project description:Myotonic dystrophy type 1 (DM1) is a dominantly inherited disorder due to a toxic gain of function of RNA transcripts containing expanded CUG repeats (CUGexp). Patients with DM1 present with multisystemic symptoms, such as muscle wasting, cognitive impairment, cataract, frontal baldness, and endocrine defects, which resemble accelerated aging. Although the involvement of cellular senescence, a critical component of aging, was suggested in studies of DM1 patient-derived cells, the detailed mechanism of cellular senescence caused by CUGexp RNA remains unelucidated. Here, we developed a DM1 cell model that conditionally expressed CUGexp RNA in human primary cells so that we could perform a detailed assessment that eliminated the variability in primary cells from different origins. To identify the pathway that induced cellular senescence, we conducted comprehensive gene expression analysis using RNA sequencing (RNA-Seq) in CUGexp+ and CUGexp− cells.

2022-04-19 | GSE196265 | GEO

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