Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting ADAR1-mediated RNA editing inhibits hepatic stellate cell activation and liver fibrosis by enhancing HSC-intrinsic IFN signaling

ABSTRACT: This study aims to characterize the RNA editome during fibrogenesis and to elucidate the role of ADAR1 in hepatic stellate cell (HSC) activation and liver fibrosis. We showed that ADAR1 ablation in primary mouse HSCs ameliorated HSC activation. Mechanistically, ADAR1 ablation led to dsRNA accumulation and activated HSC-intrinsic IFN signaling in an MDA5-dependent manner. RNA editome analysis revealed that the 3’ UTR of the pro-fibrogenic gene Col3a1 was highly edited by ADAR1, leading to mRNA stabilization and increased protein expression. Targeting ADAR1-mediated RNA editing in HSCs holds promise to prevent and treat liver fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE283569 | GEO | 2026/01/23

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Irf7 orchestrates the immunological reaction in cardiomyocytes upon Adar1 deletion

Project description:Adenosine deaminases acting on RNA (Adar1 and Adar2) catalyze I-to-A RNA editing, a post-transcriptional mechanism involved in multiple cellular functions. The role of Adar1-dependent RNA editing in cardiomyocytes (CMs) remains unclear. Here we show that conditional deletion of Adar1 in CMs results in myocarditis progressively evolving into dilated cardiomyopathy and heart failure at only 6 months of age. Adar1 depletion drives activation of interferon signaling genes (ISGs) in the absence of apoptosis and cytokine activation, and reduces the hypertrophic response of CMs upon pressure overload. Interestingly, ablation of the cytosolic sensor MDA5 prevents cardiac ISG activation and delays disease onset, but does not rescue the long-term lethal phenotype elicited by conditional deletion of Adar1. Retention of a single catalytically inactive Adar1 allele in CMs, in combination with MDA5 depletion, however, completely restores the cardiac function and prevents heart failure. Finally, ablation of interferon regulatory factor 7 (Irf7) attenuates the phenotype of Adar1-deficient CMs to a similar extent as MDA5 depletion, highlighting Irf7 as the main regulator of the immune response triggered by lack of Adar1 in CMs.

2022-08-24 | PXD024974 | Pride

Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver -Spatial Transcriptomics

Project description:ADAR1 is thought to be an immune suppressor maintaining self-tolerance to endogenous nucleic acids. Lack of ADAR1 results in MDA5 (Ifih1) activation and MDA5 deletion rescues ADAR1 null embryonic lethality. We generated liver specific ADAR1; MDA5 double KO mice and performed high throughput sequencing to investigate hepatic inflammation in these mice. Spatial transcriptomics (Visium, 10x Genomics) was performed on FFPE mice liver tissues. Constructed libraries were sequenced on the Novaseq 6000 platform. Over 250 million pairs of mappable reads for each sample were obtained.

2024-05-28 | GSE228195 | GEO

Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver -bulk RNA-seq

Project description:ADAR1 is thought to be an immune suppressor maintaining self-tolerance to endogenous nucleic acids. Lack of ADAR1 results in MDA5 (Ifih1) activation and MDA5 deletion rescues ADAR1 null embryonic lethality. We generated liver specific ADAR1; MDA5 double KO mice and performed high throughput sequencing to investigate hepatic inflammation in these mice. Bulk RNA was sequenced on the HiSeq X platform. Over 100 million pairs of mappable reads for each sample were obtained.

2024-05-28 | GSE225175 | GEO

Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver -scRNAseq

Project description:ADAR1 is thought to be an immune suppressor maintaining self-tolerance to endogenous nucleic acids. Lack of ADAR1 results in MDA5 (Ifih1) activation and MDA5 deletion rescues ADAR1 null embryonic lethality. We generated liver specific ADAR1; MDA5 double KO mice and performed high throughput sequencing to investigate hepatic inflammation in these mice. Single cell RNA sequencing was performed on cells isolated from mice livers. Constructed libraries were sequenced on the HiSeq X platform. Over 100 million pairs of mappable reads for each sample were obtained.

2024-05-28 | GSE227092 | GEO

Glycolysis in hepatic stellate cells coordinates fibrogenic extracellular vesicle release spatially to amplify liver fibrosis

Project description:Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nano-sized extracellular vesicles (EVs) and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated upregulation of EV-related pathways in the liver pericentral zone, which was abrogated by the glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs upregulated the expression of EV-related genes such as RAB31 by enhancing histone-3-lysine-9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.

2024-05-16 | PXD050337 | Pride

Human hepatic stellate cell-derived extracellular vesicles LC-MSMS

Project description:Activation and migration of hepatic stellate cells (HSCs) followed by matrix deposition are characteristics of liver fibrosis. Several studies have shown the importance of hepatocyte and endothelial cell-derived extracellular vesicles (EVs) in liver pathobiology. However, less is known about the role of HSC-derived EVs in liver diseases. In this study, we investigated the molecules released through HSC-derived EVs and whether these can promote fibrosis.

2018-10-18 | PXD007258 | Pride

ADAR1-isoforms specific editome: RNA sequencing of A-to-I editing deficient mouse embryonic fibroblast transfected with ADAR1p150 or ADAR1p110 or RFP.

Project description:Adenosine deaminase acting on RNA (ADAR) (also known as ADAR1) promotes A-to-I conversion in double-stranded and highly structured RNAs. ADAR1 has two isoforms transcribed from different promoters: ADAR1p150, which is mainly cytoplasmic and interferon-inducible, and constitutively expressed ADAR1p110 that is primarily localized in the nucleus. Mutations in ADAR1 cause Aicardi – Goutières syndrome (AGS), a severe autoinflammatory disease in humans associated with aberrant IFN production. In mice, deletion of ADAR1 or selective knockout of the p150 isoform alone leads to embryonic lethality driven by overexpression of interferon-stimulated genes. This phenotype can be rescued by concurrent deletion of cytoplasmic dsRNA-sensor MDA5. These findings indicate that the interferon-inducible p150 isoform is indispensable and cannot be rescued by the ADAR1p110 isoform. Nevertheless, editing sites uniquely targeted by ADAR1p150 but also mechanisms of isoform- specificity remain elusive. To identify ADAR1 isoform-specific ‘editome’, we transfected A-to-I editing deficient mouse embryonic fibroblasts (MEFs) with ADAR1p150- or ADAR1p110- or RFP-editing negative control. We subjected the samples to RNA sequencing and detected editing at known-editing sites.

2021-11-17 | GSE188842 | GEO

ADAR1 utilizes independent mechanisms to suppress MDA5 and PKR activation by cellular double-stranded RNA

Project description:The antiviral defense in vertebrates requires the innate immune system to sense foreign “non-self” nucleic acids while avoiding “self” nucleic acids, which is accomplished by an intricate system. Cellular double-stranded RNAs (dsRNAs) are edited by the RNA editing enzyme ADAR1 to prevent their dsRNA structure pattern from being recognized as viral dsRNA. Lack of RNA editing by ADAR1 enables activation of MDA5, a cytosolic dsRNA sensor, by cellular dsRNA. Additional RNA editing- independent functions of ADAR1 have been proposed, but the specific mechanism remains elusive. Here we demonstrate that RNA binding by ADAR1, independent of its editing activity, restricts the activation of PKR, another cytosolic dsRNA sensor, by cellular dsRNA. Mechanistically, the loss of ADAR1 editing caused MDA5 activation to induce interferon signaling, while a lack of ADAR1 protein or its dsRNA binding ability led to PKR activation, with subsequent stress granule formation and proliferation arrest. Based on these findings we rescued the Adar1−/− mice from embryonic lethality to adulthood by deleting both MDA5 and PKR, in contrast to the limited rescue of Adar1−/− mice by removing MDA5 or PKR alone. Our findings reveal a multifaceted contribution of ADAR1 in regulating the immunogenicity of “self” dsRNAs. Furthermore, ADAR1 is an immuno-oncology target for drug development, and the separation of ADAR1’s RNA editing and binding functions provides mechanistic insights for such developments.

2023-10-03 | GSE198386 | GEO

Lineage-specific Transcription Factors suppress activation of Hepatic Stellate Cells during Liver Fibrosis

Project description:Development of liver fibrosis is associated with activation of quiescent Hepatic Stellate Cells (qHSCs) into Collagen Type I-producing myofibroblasts (aHSCs). Cessation of liver injury often results in fibrosis resolution and inactivation of aHSCs/myofibroblasts into a quiescent-like state (iHSCs). To identify the molecular drivers of these HSC phenotypes, we investigated the global gene expression and epigenetic changes in H3K4me2 and H3K27ac marks of primary murine and human HSCs. Motif enrichment identified ETS1/2, GATA4/6, and IRF1/2 transcription factors (TFs) as putative regulators of the HSC lineage identity in murine and human HSCs. shRNA-knockdown of these TFs resulted in marked upregulation of fibrogenic and inflammatory genes and a loss of HSC-specific phenotype in targeted murine HSCs. In support, in vivo HSC-specific ablation of GATA4, GATA6, and ETS1, and ETS1 target genes NF1 (neurofibromin 1) and PPARγ exacerbated development of carbon tetrachloride (CCl4)-induced liver fibrosis in LratΔGATA6, LratETS1+/-, LratΔNF1, and LratΔPPARγ mice (vs wt littermates), but only LratΔGATA6, and LratΔPPARγ mice exhibited a defect in fibrosis resolution due to the lack of HSC inactivation. Therapeutic administration of a PPARγ agonist accelerated regression of liver fibrosis in CCl4-induced wt, but not in LratΔPPARγ mice, suggesting that PPARγ signaling in HSCs is critical for HSC inactivation and regression of liver fibrosis. Common transcription factors determine the phenotype of mouse and human HSCs. Similar to murine HSCs, human aHSCs can revert into a quiescent-like, inactivated phenotype. GATA4, GATA6, and PPARγwere identified as an important driver of human HSC inactivation.

2020-01-27 | GSE140641 | GEO

Quantitative proteomics analysis of liver from LONP1 Knockout mice

Project description:The mechanisms of hepatic stellate cell (HSC) activation and the development of liver fibrosis remains largely unknow. Here, we revealed a fibrosis related mechanism of hepatocytes-HSCs crosstalk regulated by hepatocyte LONP1. We demonstrate that hepatocyte LONP1 expression is decreased in HFD-fed mice and MASH patients. Liver-specific LONP1 deficiency increases orotic acid level and aggravates MASH-induced liver fibrosis in mice. We have identified DHODH as a substrate that is selectively degraded by LONP1 in an ATP-dependent manner. Moreover, activation of LONP1 reduces orotic acid levels and alleviates MASH-induced fibrosis in mice. Mechanistically, LONP1 mediates DHODH turnover, maintaining lower orotic acid levels to inhibit ATF3-mediated HSC proliferation and activation, thereby preventing liver fibrosis. Furthermore, plasma orotic acid levels are negatively correlated with liver LONP1 levels in humans. Therefore, targeting LONP1-mediated hepatocyte-HSC communication may represent a promising therapeutic strategy for MASH-induced liver fibrosis.

2025-09-23 | PXD055467 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data