AntimiR blocking of miR-23b and -218 corrects myotonic dystrophy primary cell defects over a wide range of CTG repeat expansions.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA994907 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25281449_1.fastq.gz | Fastqsanger.gz | |||
| SRR25281449_2.fastq.gz | Fastqsanger.gz | |||
| SRR25281450_1.fastq.gz | Fastqsanger.gz | |||
| SRR25281450_2.fastq.gz | Fastqsanger.gz | |||
| SRR25281451_1.fastq.gz | Fastqsanger.gz |
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Project description:This study tested candidate therapeutic antimiRs in a comprehensive new collection of primary myoblasts derived from myotonic dystrophy type 1 (DM1) patients. DM1 is caused by genetically unstable CTG repeat expansions in the DMPK gene and has multiple clinical presentations, likely because of variable repeat sizes at the tissue and organ levels. Expanded DMPK transcripts deplete Muscleblind-Like Splicing Regulator protein MBNL1, which in turn causes DM1 symptoms. A promising therapeutic approach increases the expression of MBNL1 by blocking natural repressors miR-23b and miR-218 employing antimiRs with chemical modifications designed for a better pharmacological profile in humans. In untreated primary cells, we demonstrate that upregulated therapeutic targets miR-23b and miR-218 and reduced MBNL1 protein levels inversely correlate with CTG repeat size, supporting that active MBNL1 protein repression synergizes with the sequestration by CUG repeats in DM1. Upon treatment with novel antimiRs, multiple readouts of RNA toxicity associated with typical DM1 alterations improved. MBNL1-dependent exon inclusions, and myoblast fusion and myotube area defects, showed robust correction over a wide range of CTG expansions. Unexpectedly, antimiR treatment also reduced DMPK transcript levels and the number of ribonuclear aggregates. Based on these data, we selected a leading antimiR for further transcriptomics characterization and demonstrated that it reversed up to 68% of dysregulated genes. The study revealed that the candidate antimiRs could provide therapy to clinically relevant DM1 forms over a wide range of repeat sizes and genetic backgrounds by simultaneously reducing MBNL1 sequestration and derepressing protein synthesis.
2024-05-01 | GSE237411 | GEO
Project description:Aberrant expression of oncomicroRNAs and tumor suppressor miRNAs (tsmiRs) contributes to the carcinogenesis and progression of cervical cancer (CC). miR-124-3p, miR-23b-3p, and miR-218-5p are tsmiRs that modulate oncogenes regulating cellular processes implicated in CC progression. This research aimed to explore transcriptomic changes in C-33A and CaSki cells following the overexpression of miR-124-3p, miR-23b-3p, and miR-218-5p, and to identify the biological processes (BPs) and pathways modulated by differentially expressed genes (DEGs). A total of 100 nM of miR-124-3p, miR-23b-3p, and miR-218-5p mimetics were transfected into C-33A and CaSki cells, and transcriptome changes were analyzed using RNA-seq. The Galaxy and R-Studio platforms were employed to identify DEGs, while BPs and pathways regulated by DEGs were identified through the DAVID platform. Transcriptional changes revealed both differences and similarities between cell lines and miRNAs. In C-33A cells, miR-124-3p and miR-218 regulated direct and indirect targets involved in the cell cycle and apoptosis. In CaSki cells, apoptosis and viral carcinogenesis were regulated by genes modulated directly or indirectly by miR-124-3p and miR-23b-3p. These tsmiRs demonstrated synergistic activity, regulating multiple transcripts that modulate processes and pathways involved in CC progression, with or without HPV. These findings suggest that miR-124-3p, miR-23b-3p, and miR-218-5p may represent promising therapeutic alternatives for CC treatment.
2024-11-13 | GSE279412 | GEO
Project description:Dysregulation of tumor suppressor miRNAs (tsmiRs) is associated with tumor progression in cancer. miR-23b-3p, miR-218-5p and miR-124-3p are tsmiRs in cervical cancer (CC) and regulate the translation of genes involved in metastasis-related biological processes. Objective. To analyze transcriptome changes in cervical cancer cell lines (C-33A HPV-negative and CaSki HPV-positive) overexpressing miR-23b-3b+miR-218-5p+miR-124-3p, to identify specific target transcripts common to all three miRNAs, as well as signaling pathways and cellular processes related to tumor progression. Methods. The transcriptome of C-33A and CaSki cells transfected with miR-23b-3b+miR-218-5p+miR-124-3p was analyzed by RNA-seq. Differentially expressed genes (DEGs) were subjected to Gene Ontology analysis on the DAVID platform. The function of under-regulated genes was analyzed on the GEPIA 2.0, Kaplan-Meier plotter and STRING platforms. On the TargetScanHuman platform it was determined which transcripts have MREs for miR-23b-3p, miR-218-5p and/or miR-124-3p in their 3`UTR region. Results. Simultaneous overexpression of miR-218-5p, miR-124-3p and miR-23b-3p induced changes in global gene expression in C-33A and CaSki cells. In C-33A cells, DEGs included 45 over- and 172 under-regulated transcripts; in CaSki, 125 transcripts were over- and 84 under-regulated. The under-regulated transcripts enrich proliferation, migration, apoptosis and angiogenesis; 20 of these genes are associated with overall survival (OS) in women with CC, and 18 of the 20 mRNAs have MREs for one, two or all three miRNAs. Conclusions. miR-23b-3b+miR-218-5p+miR-124-3p, differentially modify global gene expression in C-33A and CaSki cells. The results indicate that these miRNAs act synergistically and modulate CC progression through individual and shared targets by two or all three miRNAs.
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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.
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Project description:Expression of the miR-34 family (miR-34a, -34b, -34c) is elevated in settings of heart disease, and inhibition with antimiR-34a/antimiR-34 has emerged as a promising therapeutic strategy. Under chronic cardiac disease settings, targeting the entire miR-34 family is more effective than targeting miR-34a alone. The identification of transcription factor (TF)-miRNA regulatory networks has added complexity to understanding the therapeutic potential miRNA-based therapies. Here, we sought to determine whether antimiR-34 targets secondary miRNAs via TFs which could contribute to antimiR-34-mediated protection. Using miRNA-Seq we identified differentially regulated miRNAs in hearts from mice with cardiac pathology due to transverse aortic constriction (TAC), and these miRNAs were also regulated by antimiR-34. Two clusters of stress-responsive miRNAs were classified as “pathological” and “cardioprotective”. Using ChIPBase we identified 45 TF binding sites on the promoters of “pathological” and “cardioprotective” miRNAs, and 5 represented direct targets of miR-34, with the capacity to regulate other miRNAs. The expression of two “pathological” miRNAs (let-7e and miR-31) was independently experimentally validated in hearts from antimiR-34 treated TAC mice, and may explain why targeting the entire miR-34 family is more effective than targeting miR-34a alone. AntimiR-34 regulates the expression of other miRNAs and this has significant implications for drug development.
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