ADAR1 RNA editing quenches innate immune activation in endothelial cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE174216 | GEO | 2021/12/27
REPOSITORIES: GEO
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Project description:The ADAR RNA editing enzymes deaminate adenosine bases to inosines in cellular RNAs, recoding open reading frames. Human ADAR1 mutations cause Aicardi-Goutieres Syndrome (AGS) and Adar1 mutant mice showing an aberrant interferon response and death by embryonic day E12.5 model the human disease. Searches have not identified key ADAR1 RNA editing sites recoding immune/haematopoietic proteins but editing is widespread in Alu sequences. We show that Adar1 embryonic lethality is rescued in Adar1; Mavs double mutant mice in which general antiviral responses to cytoplasmic dsRNA are prevented. We propose that inosine bases are epigenetic marks identifying cellular RNA as innate immune ÒselfÓ. Consistent with this idea we show that an editing-active cytoplasmic ADAR is required to prevent aberrant immune responses in Adar1 mutant mouse embryo fibroblasts. No dramatic increase in repetitive transcripts is observed. AGS mutations in ADAR1 affect editing by the interferon-inducible cytoplasmic ADAR1 isoform. RNA-seq expression profiling in Adar1 and Adar1/Mavs knockout mice embryos.
2014-12-19 | E-GEOD-62917 | biostudies-arrayexpress
Project description:Enterovirus infection has long been suspected as a possible trigger for type 1 diabetes. Upon infection, viral double-stranded RNA (dsRNA) is recognized by membrane and cytosolic sensors that orchestrate the type I interferon signaling and the recruitment of innate immune cells to the pancreatic islets. In this context, adenosine deaminase acting on RNA 1 (ADAR1) editing plays an important role in dampening the immune response by inducing adenosine mispairing, destabilizing the RNA duplexes and thus preventing an excessive immune activation. Here, we evaluated the role of ADAR1 in human pancreatic b cells and determined the impact of type 1 diabetes pathophysiological environment on ADAR1-dependent RNA editing. We show that both IFNα or IFNɣ/IL1β stimulation promotes ADAR1 expression and increases the A-to-I RNA editing of Alu-Containing mRNAs in EndoC-bH1 cells as well as primary human islets. We demonstrate that ADAR1 overexpression inhibits the type I interferon response signaling, while ADAR1 silencing potentiates IFNα effects. In addition, ADAR1 overexpression triggers the generation of alternative spliced RNAs, highlighting a novel role for ADAR1 as regulator of the b cell transcriptome under inflammatory conditions.
2022-11-23 | GSE214851 | GEO
Project description:Adenosine deaminase acting on RNA 1 (ADAR1) is the master RNA editor, catalyzing the deamination of adenosine to inosine. RNA editing is vital for preventing abnormal activation of cytosolic nucleic acid sensing pathways by self-double-stranded RNAs. Here we determine by parallel analysis of RNA secondary structure sequencing (PARS-seq), the global RNA secondary structure changes in ADAR1 deficient cells. Surprisingly, ADAR1 silencing resulted in a lower global double-stranded to single-stranded RNA ratio, suggesting that A-to-I editing can stabilize a large subset of imperfect RNA duplexes. The duplexes destabilized by editing are composed of vastly complementary inverted Alus found in untranslated regions of genes with vital biological processes, including housekeeping functions and type-I interferon responses. They are predominantly cytoplasmic and generally demonstrate higher ribosomal occupancy. Our findings imply that the editing effect on RNA secondary structure is context dependent and underline the intricate regulatory role of ADAR1 on global RNA secondary structure.
2017-06-25 | GSE100210 | GEO
Project description:Adenosine-to-Inosine (A-to-I) editing of double stranded RNA (dsRNA) is an essential modifier of dsRNA immunogenicity. Loss of Adenosine deaminase acting on RNA 1 (ADAR1), or its A-to-I editing activity, triggers a lethal MDA5-dependent autoinflammatory response to endogenous unedited dsRNA. We performed a genome-wide suppressor screen to map the genetic landscape regulating the response to a loss of ADAR1 mediated A-to-I editing. This identified that the interacting proteins GGNBP2, CNOT10 and CNOT11 regulate immunogenic sensing following loss of A-to-I editing. GGNBP2 acts between transcription and cytoplasmic MDA5 sensing. Loss of GGNBP2 modified the distribution of dsRNA within cells, reducing the cytoplasmic dsRNA load and preventing induction of type I IFN and lethal autoinflammation. GGNBP2, CNOT10 and CNOT11 are novel regulators of the cellular response to unedited dsRNA.
2024-11-21 | GSE234570 | GEO
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
Project description:The project aims to evaluate the contribution of ADAR1 RNA editing to B cell lymphomagenesis, specifically in diffuse large B cell lymphoma (DLBCL). Within our DLBCL cohort, RNA editing targets transcripts within known lymphoma-driving pathways such as apoptosis, p53 and NF-kB signaling, as well as the previously unrecognized RIG-I-like pathway. In the latter context, we show that ADAR1-mediated editing in the MAVS transcript correlates with increased MAVS protein expression levels, associating with increased interferon/NF-kB signaling and increased T cell exhaustion. To confirm this mechanism, we have performed LC-MSMS analysis on a DLBCL cell line (RCK8) in the presence or absence of ADAR1 (Figure S11D ). Additionally, using targeted RNA base editing tools to restore editing within MAVS 3'UTR in ADAR1-deficient cells, we demonstrate that editing is likely to be causal to an increase in downstream signaling in the absence of activation by canonical nucleic acid receptor sensing. To confirm that this signaling increase depends on an increase of MAVS protein upon specific editing, we have performed LC-MSMS analysis on the same samples (Figure 4G).
2023-07-20 | PXD041549 | Pride
Project description:The ADAR RNA editing enzymes deaminate adenosine bases to inosines in cellular RNAs, recoding open reading frames. Human ADAR1 mutations cause Aicardi-Goutieres Syndrome (AGS) and Adar1 mutant mice showing an aberrant interferon response and death by embryonic day E12.5 model the human disease. Searches have not identified key ADAR1 RNA editing sites recoding immune/haematopoietic proteins but editing is widespread in Alu sequences. We show that Adar1 embryonic lethality is rescued in Adar1; Mavs double mutant mice in which general antiviral responses to cytoplasmic dsRNA are prevented. We propose that inosine bases are epigenetic marks identifying cellular RNA as innate immune ÒselfÓ. Consistent with this idea we show that an editing-active cytoplasmic ADAR is required to prevent aberrant immune responses in Adar1 mutant mouse embryo fibroblasts. No dramatic increase in repetitive transcripts is observed. AGS mutations in ADAR1 affect editing by the interferon-inducible cytoplasmic ADAR1 isoform.
2014-12-19 | GSE62917 | GEO
Project description:ADAR1 is an interferon (IFN) inducible RNA editing enzyme that converts adenosine (A) to inosine (I). Here we identified ADAR1 and ADAR1p150 specific editing events by conducting RNA-seq on WT, ADAR1 KO, and ADAR1p150 KO cells.
2018-02-09 | GSE99249 | GEO
Project description:The Adar1 deaminase inactive mutant mouse tissue samples were obtain from the Walkley lab as described in http://www.ncbi.nlm.nih.gov/pubmed/26275108. We performed mmPCR-seq on the samples and measured the editing levels of.
2017-10-01 | GSE87068 | GEO
Project description:Adenosine to Inosine (A-to-I) RNA editing is a site-specific modification of RNA transcripts, catalyzed by members of the ADAR (Adenosine Deaminase Acting on RNA) protein family. RNA editing occurs in human RNA in thousands of different sites. Some of the sites are located in protein-coding regions but the majority is found in non-coding regions, such as 3âUTRs, 5âUTRs and introns - mainly in Alu elements. While editing is found in all tissues, the highest levels of editing are found in the brain. It was shown that editing levels within protein-coding regions are increased during embryogenesis and after birth and that RNA editing is crucial for organism viability as well as for normal development. In this study we characterized the A-to-I RNA editing phenomenon during neuronal and spontaneous differentiation of human embryonic stem cells (hESCs). We identified high editing levels of Alu repetitive elements in hESCs and demonstrated a global decrease in editing levels of non-coding Alu sites when hESCs are differentiating, particularly into the neural lineage. Using RNA interference, we showed that the elevated editing levels of Alu elements in undifferentiated hESCs are highly dependent on ADAR1. DNA microarray analysis showed that ADAR1 knockdown has a global effect on gene expression in hESCs and leads to a significant increase in RNA expression levels of genes involved in differentiation and development processes, including neurogenesis. Taken together, our data suggest that A-to-I editing of Alu sequences plays a role in the regulation of hESC early differentiation decisions. Two samples, One control and the second treated
2010-07-29 | E-GEOD-19719 | biostudies-arrayexpress