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Specific silencing of pathogenic mRNA by a novel compact RNA-targeting tool TaqTth-hpRNA

ABSTRACT: Specific silencing of pathogenic mRNA by a novel compact RNA-targeting tool TaqTth-hpRNA

PROVIDER: PRJNA990747 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25117319.fastq.gz	Fastqsanger.gz
	SRR25117320.fastq.gz	Fastqsanger.gz
	SRR25117321.fastq.gz	Fastqsanger.gz
	SRR25117322.fastq.gz	Fastqsanger.gz
	SRR25117323.fastq.gz	Fastqsanger.gz

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Similar Datasets

Specific silencing of pathogenic mRNA by a novel compact RNA-targeting tool TaqTth-hpRNA

Project description:Pathogenic allele silencing is a promising treatment for genetic hereditary diseases. However, the concern about the specificity of present RNA-knockdown strategies has limited their in vivo applications. Here a TaqTth-hpRNA system consisting of a small, chimeric protein (TaqTth) and hairpin-RNA probe (hpRNA) is provided. The TaqTth-hpRNA showed a high-specific knockdown against targeted mRNA with minimal flanking sequence-motif requirement and less cell viability damage, then was applied to mutant APPswe mRNA silencing without altering the wild-type APP mRNA in Alzheimer’s disease. Notably, the combination of the TaqTth and human apolipoprotein E 2 (APOE2) overexpression encoded in a single AAV vector is available due to the compact size of TaqTth, and showed stronger inhibition of pathologies in the mouse model. Altogether, we provided the basis for a small RNA-targeting tool with high selectivity, minimal flanking sequence-motif requirement, less cell viability damage and potentially being an alternative in therapeutic applications.

2024-06-30 | GSE236392 | GEO

Specific silencing of pathogenic mRNA by a novel compact RNA-targeting tool TaqTth-hpRNA [Amplicon sequencing]

2024-06-20 | GSE269593 | GEO

Specific silencing of pathogenic mRNA by a novel compact RNA-targeting tool TaqTth-hpRNA [RNA-seq]

2024-06-20 | GSE269592 | GEO

TaqTth-hpRNA: a novel compact RNA-targeting tool for specific silencing of pathogenic mRNA.

Project description:Pathogenic allele silencing is a promising treatment for genetic hereditary diseases. Here, we develop an RNA-cleaving tool, TaqTth-hpRNA, consisting of a small, chimeric TaqTth, and a hairpin RNA guiding probe. With a minimal flanking sequence-motif requirement, in vitro and in vivo studies show TaqTth-hpRNA cleaves RNA efficiently and specifically. In an Alzheimer's disease model, we demonstrate silencing of mutant APPswe mRNA without altering the wild-type APP mRNA. Notably, due to the compact size of TaqTth, we are able to combine with APOE2 overexpression in a single AAV vector, which results in stronger inhibition of pathologies.

| S-EPMC11229350 | biostudies-literature

Brain-wide AAV-mediated silencing of prion protein by a compact epigenetic editor

Project description:Prion disease is caused by misfolding of the prion protein (PrP) into pathogenic self-propagating conformations, leading to rapid onset dementia and death. However, elimination of endogenous PrP can halt prion disease progression. Here, we describe CHARM, a compact, enzyme-free epigenetic editor capable of silencing transcription through programmable targeted DNA methylation. Using a histone H3 tail-Dnmt3l fusion, CHARM recruits and activates the endogenous DNA methyltransferases, thereby reducing transgene size and bystander effects. When delivered to the mouse brain by an adeno-associated viral (AAV) vector, PRNP-targeted CHARM ablates PrP expression across the brain. We temporally limit editor expression by implementing a kinetically-tuned self-silencing approach. CHARM represents a broadly applicable strategy to programmably prevent expression of pathogenic proteins, including those implicated in other neurodegenerative diseases.

2024-05-03 | GSE255987 | GEO

Mismatch hpRNA prevents intrinsic self-silencing and enhances RNAi stability

Project description:Hairpin RNA (hpRNA) transgenes, with a perfect inverted-repeat (IR) DNA, have been the most successful RNA interference (RNAi) method in plants. Here we show that hpRNA transgenes were invariably methylated in the IR DNA and the adjacent promoter, causing transcriptional self-silencing and preventing the full potential of RNAi. Nucleotide substitutions in the sense sequence, which disrupts the perfect IR DNA structure, were sufficient to prevent the intrinsic DNA methylation resulting in more uniform and persistent RNAi. Substituting all cytosine (C) with thymine (T) nucleotides, in a G:U hpRNA design, prevented DNA methylation and self-silencing but still allowed for the formation of perfect hpRNA due to G:U wobble base-pairing. The G:U design induces effective RNAi in 90-96% of transgenic lines, compared to 57-65% for the traditional hpRNA design. Furthermore, while a traditional hpRNA transgene showed increasing DNA methylation and self-silencing from cotyledons to true leaves, the G:U transgenes avoided this developmental progression of self-silencing and induced RNAi throughout plant growth. The G:U and traditional hpRNA transgenes generated small interfering RNA (siRNA) with different 5’ phosphorylation, which resembled the endogenous tasiRNA and miRNA, respectively. Furthermore, our results suggest that siRNAs from the two transgene designs function differently to induce target DNA methylation, one (from traditional hpRNA) through the canonical RdDM pathway and the other (G:U hpRNA) a non-canonical pathway. Our study not only revealed a methylation-resistant RNAi transgene design but also provided new mechanistic insights into small RNA biogenesis and function in plants

2022-03-31 | GSE178565 | GEO

Brain-wide AAV-mediated silencing of prion protein by a compact epigenetic editor

Project description:Brain-wide AAV-mediated silencing of prion protein by a compact epigenetic editor

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Small RNA from Arabidopsis thaliana with RNA silencing directed to Chalcone Synthase (At5G13930) by a hairpin RNA, a 21-nt artificial miRNA and a 22-nt artificial miRNA in the pap1-D over-expressing background

Project description:22-nucleotide (nt) microRNAs (miRNAs) derived from asymmetric duplexes trigger trans-acting phased small interfering RNA (tphasiRNA) production from complementary targets. Here we investigate the efficacy of 22-nt artificial miRNA (amiRNA) mediated RNA silencing relative to conventional hairpin RNA (hpRNA) and 21-nt amiRNA mediated RNA silencing. CHALCONE SYNTHASE (CHS) was selected as a target in Arabidopsis thaliana due to the obvious and non-lethal loss of anthocyanin accumulation upon widespread RNA silencing. Over-expression of CHS in the pap1-D background facilitated visual detection of both local and systemic RNA silencing. RNA silencing was initiated in leaf tissues from hpRNA and amiRNA plant expression vectors under the control of an Arabidopsis RuBisCo small subunit 1A promoter (SSU). In this system, hpRNA expression triggered CHS silencing in most leaf tissues but not in roots or seed coats. Similarly, 21-nt amiRNA expression from symmetric miRNA/miRNA* duplexes triggered CHS silencing in all leaf tissues but not in roots or seed coats. However, 22-nt amiRNA expression from an asymmetric duplex triggered CHS silencing in all tissues, including roots and seed coats, in the majority of plant lines. This widespread CHS silencing required RNA DEPENDENT RNA POLYMERASE6 mediated accumulation of phasiRNAs from the endogenous CHS transcript. These results demonstrate the efficacy of asymmetric 22-nt amiRNA-directed RNA silencing and associated phasiRNA production and activity, in mediating widespread RNA silencing of an endogenous target gene. Asymmetric 22-nt amiRNA directed RNA silencing requires little modification of existing amiRNA technology and is expected to be effective in suppressing other genes and/or members of gene families. sRNA sequencing from aerial tissues of 3-week old plants grown on MS media

2013-10-14 | E-GEOD-49792 | biostudies-arrayexpress

Mismatch hpRNA prevents intrinsic self-silencing and enhances RNAi stability

Project description:Mismatch hpRNA prevents intrinsic self-silencing and enhances RNAi stability

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PRDM16 Functions as A Compact Myocardium-Enriched Transcription Factor Required to Maintain Compact Myocardial Cardiomyocyte Identity in Left Ventricle (Spatial Transcriptomics)

Project description:The loss of compact myocardial cardiomyocyte (compact CM) identity suggests that PRDM16 deficiency may dramatically alter the cellular composition in left ventricular (LV) compact myocardium. To test this hypothesis, we performed single-cell RNA-seq (scRNA-seq) to examine gene dysreulation in Prdm16cKO heart. We also performed Visium Spatial Transcriptomics (ST) to facilitate mapping CM clusters to their original locations in the heart. As a result, we were able to demonstrate gene misregulation in Prdm16cKO mouse mainly occurred in LV compact CM.

2021-12-20 | GSE179392 | GEO

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