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Knockdown of circular RNAs using LNA-modified antisense oligonucleotides

ABSTRACT: Knockdown of circular RNAs using LNA-modified antisense oligonucleotides

PROVIDER: PRJNA607690 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11119393_1.fastq.gz	Fastqsanger.gz
	SRR11119393_2.fastq.gz	Fastqsanger.gz
	SRR11119394_1.fastq.gz	Fastqsanger.gz
	SRR11119394_2.fastq.gz	Fastqsanger.gz
	SRR11119395_1.fastq.gz	Fastqsanger.gz

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Knockdown of circular RNAs using LNA-modified antisense oligonucleotides

Project description:Circular RNAs (circRNAs) constitute an abundant class of covalently closed non-coding RNA molecules that are formed by backsplicing from eukaryotic protein-coding genes. Recent studies have shown that circRNAs can act as microRNA or protein decoys as well as transcriptional regulators. However, the functions of most circRNAs are still poorly understood. Because circRNA sequences overlap with their linear parent transcripts, depleting specific circRNAs without affecting host gene expression remains a challenge. Here, we assessed the utility of LNA-modified antisense oligonucleotides (ASOs) to knock down circRNAs for loss-of-function studies. We identified 5807 circRNAs in total RNA sequencing data from 4 liver cancer cell lines and used the back splice junction (BSJ) sequences of 7 validated circRNAs as target sites for designing different LNA-modified ASOs for circRNA knockdown. We found that while most RNase H-dependent gapmer ASOs mediate effective knockdown of their target circRNAs, some gapmers reduce the levels of the linear parent transcript and may also cause degradation of unintended off-targets. The circRNA targeting specificity can be enhanced using design-optimized gapmer ASOs or LNA/DNA mixmer ASOs, which display potent and specific circRNA knockdown with a minimal effect on the host genes or predicted off-targets. In summary, our results demonstrate that LNA-modified ASOs complementary to BSJ sequences mediate robust knockdown of circRNAs in vitro and, thus, represent a useful tool to explore the biological roles of circRNAs in loss-of-function studies in cultured cells and animal models.

2022-11-01 | GSE145592 | GEO

Gene expression analysis in liver collected from mice administered non-toxic, toxic, or severely toxic LNA sequences

Project description:Development of LNA gapmers, antisense oligonucleotides used for efficient inhibition of target RNA expression, is limited by non-target mediated hepatotoxicity issues. In the present study, we investigated hepatic transcription profiles of mice receiving non-toxic and toxic LNA gapmers after a single and repeat administration.

2014-01-08 | GSE53230 | GEO

Targeting Smyd3 by antisense oligonucleotides attenuates liver tumor growth

Project description:We investigated whether pharamacological inhibition of Smyd3 by antisense oligonucleotides (ASOs) can influence diethylnitrosamine (DEN)-induced liver cancer development. Our phenotypic analyses, among others, included gene expression profiling.

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Expression data from dosing four different antisense oligonucleotides in mice II

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Expression data from transfection of two different antisense oligonucleotides in HuH7 cells

Project description:We used microarrays to globally profile the gene expression changes observed after 24h when transfecting antisense oligonucleotides in HuH77 cells

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Expression data from transfection of 14 different antisense oligonucleotides in HuH7 cells

Project description:We used microarrays to globally profile the gene expression changes observed after 10h and 24h when transfecting antisense oligonucleotides in HuH7 cells

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Targeting Smyd3 by antisense oligonucleotides attenuates liver tumor growth

Project description:Targeting Smyd3 by antisense oligonucleotides attenuates liver tumor growth

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Phospholamban Antisense Oligonucleotides Improve Cardiac Function in Murine Cardiomyopathy

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Interaction of modified oligonucleotides with nuclear proteins, formation of novel nuclear structures and sequence-independent effects on RNA processing

Project description:Oligonucleotides and nucleic acid analogues that alter gene expression are showing therapeutic promise for selected human diseases. The modification of synthetic nucleic acids to protect against nuclease degradation and to influence drug function is common practice, however, such modifications may also confer unexpected physicochemical and biological properties. Here we report backbone-specific effects of modified oligonucleotides on subnuclear organelles, altered distribution of nuclear proteins, the appearance of novel structured nuclear inclusions, and modification of RNA processing in cultured cells transfected with antisense oligonucleotides on a phosphorothioate backbone. Phosphodiester and phosphorodiamidate morpholino oligomers elicited no such consequences. Disruption of subnuclear structures and proteins elicit severe phenotypic disturbances, revealed by transcriptomic analysis of fibroblasts exhibiting such disruption. These data suggest that the toxic effects and adverse events reported after clinical evaluation of phosphorothioate nucleic acid drugs may be mediated, at least in part, by non-specific interaction of nuclear components with the phosphorothioate backbone. The effects of antisense oligonucleotide transfection on morphology of subnuclear organelles, localisation of nuclear proteins and impact on RNA processing were examined in primary human cells.

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Structure Activity Relationships of α-L-LNA Modified Phosphorothioate Gapmer Antisense Oligonucleotides in Animals.

Project description:We report the structure activity relationships of short 14-mer phosphorothioate gapmer antisense oligonucleotides (ASOs) modified with α-L-locked nucleic acid (LNA) and related modifications targeting phosphatase and tensin homologue (PTEN) messenger RNA in mice. α-L-LNA represents the α-anomer of enantio-LNA and modified oligonucleotides show LNA like binding affinity for complementary RNA. In contrast to sequence matched LNA gapmer ASOs which showed elevations in plasma alanine aminotransferase (ALT) levels indicative of hepatotoxicity, gapmer ASOs modified with α-L-LNA and related analogs in the flanks showed potent downregulation of PTEN messenger RNA in liver tissue without producing elevations in plasma ALT levels. However, the α-L-LNA ASO showed a moderate dose-dependent increase in liver and spleen weights suggesting a higher propensity for immune stimulation. Interestingly, replacing α-L-LNA nucleotides in the 3'- and 5'-flanks with R-5'-Me-α-L-LNA but not R-6'-Me- or 3'-Me-α-L-LNA nucleotides, reversed the drug induced increase in organ weights. Examination of structural models of dinucleotide units suggested that the 5'-Me group increases steric bulk in close proximity to the phosphorothioate backbone or produces subtle changes in the backbone conformation which could interfere with recognition of the ASO by putative immune receptors. Our data suggests that introducing steric bulk at the 5'-position of the sugar-phosphate backbone could be a general strategy to mitigate the immunostimulatory profile of oligonucleotide drugs. In a clinical setting, proinflammatory effects manifest themselves as injection site reactions and flu-like symptoms. Thus, a mitigation of these effects could increase patient comfort and compliance when treated with ASOs.Molecular Therapy - Nucleic Acids (2012) 1, e47; doi:10.1038/mtna.2012.34; published online 18 September 2012.

| S-EPMC3499693 | biostudies-other

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