RNA Leaching of Transcription Factors Disrupts Transcription in Myotonic Dystrophy

Ebralidze, Alex; Wang, Y.; Petkova, Victoria; Ebralidse, Konstantin K.; Junghans, Richard P.

doi:10.1126/science.1088679

Cited by 142 publications

(125 citation statements)

References 26 publications

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“…On the other hand, soluble mutant repeats outside of foci increased CUGBP1 in DM1. 18,28 This suggests that the misregulation of CUGBP1 function in DM1 and in DM2 might be associated with soluble CUG/CCUG repeats outside of foci. Reduction of ZNF9 in DM2 might be also associated with the accumulation of soluble CCUG repeats or nonspliced ZNF9 pre-mRNA.…”

Section: Discussionmentioning

confidence: 99%

RNA Foci, CUGBP1, and ZNF9 Are the Primary Targets of the Mutant CUG and CCUG Repeats Expanded in Myotonic Dystrophies Type 1 and Type 2

Jones

Jin

Iakova

et al. 2011

The American Journal of Pathology

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Expansions of noncoding CUG and CCUG repeats in myotonic dystrophies type 1 (DM1) and DM2 cause complex molecular pathology, the features of which include accumulation of RNA aggregates and misregulation of the RNA-binding proteins muscleblind-like 1 (MBNL1) and CUG-binding protein 1 (CUGBP1). CCUG repeats also decrease amounts of the nucleic acid binding protein ZNF9. Using tetracycline (Tet)-regulated monoclonal cell models that express CUG and CCUG repeats, we found that low levels of long CUG and CCUG repeats result in nuclear and cytoplasmic RNA aggregation with a simultaneous increase of CUGBP1 and a reduction of ZNF9. Elevation of CUGBP1 and reduction of ZNF9 were also observed before strong aggregation of the mutant CUG/CCUG repeats. Degradation of CUG and CCUG repeats normalizes ZNF9 and CUGBP1 levels. Comparison of short and long CUG and CCUG RNAs showed that great expression of short repeats form foci and alter CUGBP1 and ZNF9; however, long CUG/CCUG repeats misregulate CUGBP1 and ZNF9 much faster than high levels of the short repeats. These data suggest that correction of DM1 and DM2 might be achieved by complete and efficient degradation of CUG and CCUG repeats or by a simultaneous disruption of CUG/CCUG foci and correction of CUGBP1 and ZNF9. (Am J Pathol

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Section: Discussionmentioning

confidence: 99%

RNA Foci, CUGBP1, and ZNF9 Are the Primary Targets of the Mutant CUG and CCUG Repeats Expanded in Myotonic Dystrophies Type 1 and Type 2

Jones

Jin

Iakova

et al. 2011

The American Journal of Pathology

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“…It is thought that the decreased ClCN-1 gene expression observed in the muscle cells of patients with DM1 is due to the entrapment of Sp1 in nuclear foci containing mutant DMPK RNA, because Sp1 modulates the ClCN-1 gene promoter positively. Supporting this idea, expression of the ClCN-1 gene is restored in DM1 muscle cells by overexpression of Sp1 (Ebralidze et al, 2004). Further studies are required to fully understand the influence of mutant DMPK RNA on gene expression.…”

Section: Leaching Of Transcription Factors From Chromatinmentioning

confidence: 77%

“…However, the fact that such a mutated region is transcribed but untranslated implies that mutant RNA might play a significant role in the disease process. Supporting this hypothesis, growing pieces of evidence obtained over the past 10 years have established that DM1-mutant RNA accumulates in the nuclei, disturbing RNA splicing and gene expression through sequestering of splicing and transcription factors, respectively (Day & Ranum, 2005;Ebralidze et al, 2004).…”

Section: Introductionmentioning

confidence: 97%

“…However, Six5 knockout mice only develop cataracts that lacked the distinctive iridescent opacities characteristic of cataracts of patients with DM1 (Klesert et al, 2000). c. Data from patients as well as from transgenic mice and cell lines developed for DM1 modeling have offered compelling evidence in support of the third model, which proposes that CUG repeats in the pathogenic range fold into RNA hairpins that are not exported from the nucleus but that, instead, accumulate within ribonuclear foci, acquiring a new toxic function by trapping essential cellular RNA-binding proteins including alternative-splicing modulators and transcription factors, thus disturbing the gene-expression and alternative-splicing processes, respectively (Davis et al, 1997;Ebralidze et al, 2004;Ranum & Cooper 2006;Taneja et al, 1995).…”

Section: Rna-mediated Mechanisms Of Pathogenesismentioning

confidence: 99%

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Myotonic Dystrophy Type 1 (DM1): From the Genetics to Molecular Mechanisms

Magaña¹,

Cisneros²

2012

Muscular Dystrophy

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“…CUG-repeat expansions form double-stranded hairpins that are retained as inclusions within the nucleus. These hairpins recruit a number of transcription and splicing factors, including Muscleblind-like 1 (MBNL1) (2)(3)(4)(5)(6). Sequestration of MBNL1 originates a loss of function, which plays a key role in the development of DM1 symptoms.…”

mentioning

confidence: 99%

In vivo discovery of a peptide that prevents CUG–RNA hairpin formation and reverses RNA toxicity in myotonic dystrophy models

Garcia-Lopez

Llamusí

Orzáez

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Myotonic dystrophy type 1 (DM1) is caused by the expansion of noncoding CTG repeats in the dystrophia myotonica-protein kinase gene. Mutant transcripts form CUG hairpins that sequester RNAbinding factors into nuclear foci, including Muscleblind-like-1 protein (MBNL1), which regulate alternative splicing and gene expression. To identify molecules that target toxic CUG transcripts in vivo, we performed a positional scanning combinatorial peptide library screen using a Drosophila model of DM1. The screen identified a D-amino acid hexapeptide (ABP1) that reduced CUG foci formation and suppressed CUG-induced lethality and muscle degeneration when administered orally. Transgenic expression of natural, L-amino acid ABP1 analogues reduced CUG-induced toxicity in fly eyes and muscles. Furthermore, ABP1 reversed muscle histopathology and splicing misregulation of MBNL1 targets in DM1 model mice. In vitro, ABP1 bound to CUG hairpins and induced a switch to a single-stranded conformation. Our findings demonstrate that ABP1 shows antimyotonic dystrophy activity by targeting the core of CUG toxicity.disease model | drug discovery | non-coding RNA disease | medicinal chemistry | RNA secondary structure M yotonic dystrophy type 1 (DM1, OMIM #160900) is an autosomal dominant disease caused by the expansion of a CTG trinucleotide repeat in the 3′ untranslated region (UTR) of the dystrophia myotonica-protein kinase (DMPK) gene. Characteristic symptoms include myotonia, progressive muscle wasting, and cardiac conduction defects, among other systemic manifestations. The molecular mechanisms underlying DM1 pathogenesis are complex and affect a large number of cellular processes (1). However, most data suggest that the main triggering event is a toxic gain-of-function of the expanded CUG RNA. CUG-repeat expansions form double-stranded hairpins that are retained as inclusions within the nucleus. These hairpins recruit a number of transcription and splicing factors, including Muscleblind-like 1 (MBNL1) (2-6). Sequestration of MBNL1 originates a loss of function, which plays a key role in the development of DM1 symptoms. Mbnl1 knockout mice reproduced typical features of DM1, and overexpression of Mbnl1 in a mouse model that expressed CTG repeats reversed these phenotypes (7,8). CTGrepeat expression in mice caused misregulation of at least 156 alternative splicing events. Of these, 128 also occurred in Mbnl1 knockout animals (9-12). The splicing factor CUG-binding protein 1 (CUGBP1) is another key component in the development of DM1 phenotypes. CUGBP1 antagonizes MBNL1 activity in the regulated use of alternative exons in a number of transcripts and is abnormally upregulated in patients with DM1, further contributing to splicing misregulation (13-15).Mahadevan et al. provided the first in vivo proof-of-principle for a therapeutic strategy based on ablating toxic RNA molecules in DM1 (16). They demonstrated that expanded CTG-induced effects could be reverted if CTG-repeat transgene expression was interrupted in a DM1 mouse model. Several ...

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RNA Leaching of Transcription Factors Disrupts Transcription in Myotonic Dystrophy

Cited by 142 publications

References 26 publications

RNA Foci, CUGBP1, and ZNF9 Are the Primary Targets of the Mutant CUG and CCUG Repeats Expanded in Myotonic Dystrophies Type 1 and Type 2

RNA Foci, CUGBP1, and ZNF9 Are the Primary Targets of the Mutant CUG and CCUG Repeats Expanded in Myotonic Dystrophies Type 1 and Type 2

Myotonic Dystrophy Type 1 (DM1): From the Genetics to Molecular Mechanisms

In vivo discovery of a peptide that prevents CUG–RNA hairpin formation and reverses RNA toxicity in myotonic dystrophy models

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