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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE53230 | GEO | 2014/01/08

SECONDARY ACCESSION(S): PRJNA231176

REPOSITORIES: GEO

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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. To understand the mechanism of LNA gapmer-induced heptotoxicity in mice, we investigated the transcription profiles of liver RNA isolated from mice receiving non-toxic sequence (NTS-1), toxic sequence (TS-2), or severely toxic sequence (HTS-3) of LNA gapmers at 25 mg/kg (dose volume of 10 mL/kg) at 8, 16, or 72 hrs after a single administration (by subcutaneous injection ) using microarray analysis. We also investigated the transcription profiles of liver RNA isolated from mice receiving non-toxic sequence (NTS-1) or toxic sequence (TS-2) of LNA gapmers at 25 mg/kg (dose volume of 10 mL/kg) at 2 weeks after repeated administration (by subcutaneous injection ) using microarray analysis.

2014-01-08 | E-GEOD-53230 | biostudies-arrayexpress

Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR

Project description:Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver MicroRNA-122 (miR-122) is an abundant liver-specific miRNA, implicated in fatty acid and cholesterol metabolism as well as hepatitis C viral replication. Here, we report that a systemically administered 16-nt, unconjugated LNA (locked nucleic acid)-antimiR oligonucleotide complementary to the 5' end of miR-122 leads to specific, dose-dependent silencing of miR-122 and shows no hepatotoxicity in mice. Antagonism of miR-122 is due to formation of stable heteroduplexes between the LNA-antimiR and miR-122 as detected by northern analysis. Fluorescence in situ hybridization demonstrated uptake of the LNA-antimiR in mouse liver cells, which was accompanied by markedly reduced hybridization signals for mature miR-122 in treated mice. Functional antagonism of miR-122 was inferred from a low cholesterol phenotype and de-repression within 24 h of 199 liver mRNAs showing significant enrichment for miR-122 seed matches in their 3' UTRs. Expression profiling extended to 3 weeks after the last LNA-antimiR dose revealed that most of the changes in liver gene expression were normalized to saline control levels coinciding with normalized miR-122 and plasma cholesterol levels. Combined, these data suggest that miRNA antagonists comprised of LNA are valuable tools for identifying miRNA targets in vivo and for studying the biological role of miRNAs and miRNA-associated gene-regulatory networks in a physiological context. Keywords: compound treatment

2008-12-16 | GSE13948 | GEO

Transcription profiling of mouse after antagonism of microRNA-122 by systemically administered LNA-antimiR

Project description:Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver; MicroRNA-122 (miR-122) is an abundant liver-specific miRNA, implicated in fatty acid and cholesterol metabolism as well as hepatitis C viral replication. Here, we report that a systemically administered 16-nt, unconjugated LNA (locked nucleic acid)-antimiR oligonucleotide complementary to the 5' end of miR-122 leads to specific, dose-dependent silencing of miR-122 and shows no hepatotoxicity in mice. Antagonism of miR-122 is due to formation of stable heteroduplexes between the LNA-antimiR and miR-122 as detected by northern analysis. Fluorescence in situ hybridization demonstrated uptake of the LNA-antimiR in mouse liver cells, which was accompanied by markedly reduced hybridization signals for mature miR-122 in treated mice. Functional antagonism of miR-122 was inferred from a low cholesterol phenotype and de-repression within 24 h of 199 liver mRNAs showing significant enrichment for miR-122 seed matches in their 3' UTRs. Expression profiling extended to 3 weeks after the last LNA-antimiR dose revealed that most of the changes in liver gene expression were normalized to saline control levels coinciding with normalized miR-122 and plasma cholesterol levels. Combined, these data suggest that miRNA antagonists comprised of LNA are valuable tools for identifying miRNA targets in vivo and for studying the biological role of miRNAs and miRNA-associated gene-regulatory networks in a physiological context. Experiment Overall Design: Female NMRI mice were treated at day 2 with either 25mg/kg antimiR-122 (SPC3372) or vehicle (saline). Mice were sacrificied at day 3, 9 and 23 and liver RNA assayed. Three biological replicates for each of the six groups.

2009-01-13 | E-GEOD-13948 | biostudies-arrayexpress

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

Endothelial gene expression analysis after silencing the lncRNA GATA6-AS using LNA GapmeRs.

Project description:Endothelial gene expression analysis after silencing the lncRNA GATA6-AS using LNA GapmeRs.

| PRJNA418858 | ENA

Proteomic profile of human breast cancer cells expressing normal levels or absent of the long non-coding RNA NORAD.

Project description:We describe here the proteome of the human breast cancer cell line MDA-MB-231 expressing normal levels of the lncRNA NORAD, or after knock-down NORAD with siRNA and LNA gapmers.

2023-08-28 | PXD039920 | Pride

Implication of repeat insertion domains in the trans-activity of the long non-coding RNA ANRIL [ANRIL_LNA_Affy]

Project description:To identify the genes differentially expressed upon the knockdown of the lncRNA ANRIL using LNA GapmeRs in HEK293 cells

2021-05-26 | GSE162223 | GEO

RNA-seq to investigate gene expression profile associated with long-non coding RNA RAIN in TPC1 cells

Project description:We used RNA-seq analysis to identify gene expression profile in TPC1 cells transfected with LNA gapmers against RAIN vs control

2018-09-01 | E-MTAB-6622 | biostudies-arrayexpress

Breast cancer MCF-7 cells and MDA-MB-231 cells: LNA-antimiR-21 transfected cells vs. LNA-control transfected cells

Project description:Transcriptional profiling of breast cancer cells comparing LNA-control transfected cells with cells transfected with LNA-antimiR-21.We searched for miR-21 targets by systematic screening of mRNA profiling of LNA-antimiR-21 transfected MCF-7 cells and MDA-MB-231 cells.

2010-03-05 | GSE20627 | GEO

Long Non-Coding RNA MEG3 Promotes Angiogenesis by directly regulating integrin signaling impairing endothelial cell function [ChIP-seq]

Project description:We immunoprecipitated EZH2, together with associated chromatin isolated from the HUVECs (2 x 10^6) that were transfected with MEG3 GapmeRs (10 nM, 48 h) or a scrambled control GapmeRs (Ctr). For transfection, we used 10 nM scrambled LNA (locked nucleic acids) GapmeR control (Cat. No. 339515) or phosphorothioate antisense standard GapmeRs MEG3-lncRNA (Cat No. 339511, Qiagen). On beads crosslinked chromatin complexes were reversed, and DNA purified using QIAquick® PCR Purification Kit and quantified by Qubit HS assay (Q33230)

2024-04-12 | GSE234543 | GEO

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