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RNA editing is the essential function of ADAR1 and, in the absence of MDA5, is dispensable for normal adult homeostasis [RNAseq (Fetal Brain)]

ABSTRACT: Adenosine-to-Inosine (A-to-I) editing of dsRNA by ADAR proteins is a pervasive feature of the epitranscriptome. There are estimated to be over 100 million potential A-to-I editing sites in humans and A-to-I editing can have varying consequences for gene expression. Whilst editing resulting in protein recoding defines the role of ADAR2, ADAR1 has been proposed to have both editing-dependent and -independent functions. The relative contribution of these putative functions to ADAR1 biology is unclear. We demonstrate that the absence of ADAR1-mediated editing is well tolerated when the cytosolic dsRNA sensor MDA5 is deleted. These mice have normal hematopoiesis, tissue patterning and life span. A direct comparison of the complete deletion of ADAR1 and the specific loss of A-to-I editing activity demonstrates that RNA editing is the only essential function of ADAR1 in adult mice. Therefore, preventing MDA5 substrate formation by endogenous RNA is the essential in vivo function of ADAR1-mediated editing.

ORGANISM(S): Mus musculus

PROVIDER: GSE94388 | GEO | 2017/08/14

SECONDARY ACCESSION(S): PRJNA369544

REPOSITORIES: GEO

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RNA editing is the essential function of ADAR1 and, in the absence of MDA5, is dispensable for normal adult homeostasis [mmPCR-seq]

Project description:Adenosine-to-Inosine (A-to-I) editing of dsRNA by ADAR proteins is a pervasive feature of the epitranscriptome. There are estimated to be over 100 million potential A-to-I editing sites in humans and A-to-I editing can have varying consequences for gene expression. Whilst editing resulting in protein recoding defines the role of ADAR2, ADAR1 has been proposed to have both editing-dependent and -independent functions. The relative contribution of these putative functions to ADAR1 biology is unclear. We demonstrate that the absence of ADAR1-mediated editing is well tolerated when the cytosolic dsRNA sensor MDA5 is deleted. These mice have normal hematopoiesis, tissue patterning and life span. A direct comparison of the complete deletion of ADAR1 and the specific loss of A-to-I editing activity demonstrates that RNA editing is the only essential function of ADAR1 in adult mice. Therefore, preventing MDA5 substrate formation by endogenous RNA is the essential in vivo function of ADAR1-mediated editing.

2017-08-14 | GSE94386 | GEO

RNA editing is the essential function of ADAR1 and, in the absence of MDA5, is dispensable for normal adult homeostasis [RNAseq (Adult Brain)]

2017-08-14 | GSE94387 | GEO

The RNA editing enzyme ADAR1 is a key regulatory of innate immune responses to RNA

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

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

The RNA editing enzyme ADAR1 is a key regulatory of innate immune responses to RNA

2014-12-19 | GSE62917 | GEO

Malignant A-to-I RNA editing by ADAR1 drives T-cell acute lymphoblastic leukemia relapse via attenuating dsRNA sensing

Project description:Leukemia initiating cells (LICs) are regarded as the origin of leukemia relapse and therapeutic resistance. Identifying direct stemness determinants that fuel LIC self-renewal is critical for developing targeted approaches to eliminate LICs and prevent relapse. Here, we show that the RNA editing enzyme ADAR1 is a crucial stemness factor that promotes LIC self-renewal by attenuating aberrant double-stranded RNA (dsRNA) sensing. Elevated adenosine-to-inosine (A-to-I) editing is a common attribute of relapsed T-ALL regardless of molecular subtypes. Consequently, knockdown of ADAR1 severely inhibits LIC self-renewal capacity and prolongs survival in T-ALL PDX models. Mechanistically, ADAR1 directs hyper-editing of immunogenic dsRNA to avoid detection by the innate immune sensor MDA5. Moreover, we uncovered that the cell intrinsic level of MDA5 dictates the dependency on ADAR1-MDA5 axis in T-ALL. Collectively, our results show that ADAR1 functions as a self-renewal factor that limits the sensing of endogenous dsRNA. Thus, targeting ADAR1 presents an effective therapeutic strategy for eliminating T-ALL LICs.

2023-12-31 | GSE221112 | GEO

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

Determine the ADAR1 editome during IFN response.

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

ADAR1 regulates growth & invasion in triple-negative breast cancer

Project description:ADAR1 catalyzes Adenosine-to-Inosine (A-to-I) editing of double-stranded RNA and regulates global expression output through its interactions with RNA and other proteins. ADARs play important roles in development and disease, and previous work has shown that ADAR1 is oncogenic in a growing list of cancer types. Here we show that ADAR1 is important for growth and invasion in triple negative breast cancer cells, as ADAR1 loss yields reduced growth, migration & invasion, and mammosphere formation. Global RNA-seq analyses demonstrate that ADAR1 regulates both coding and non-coding targets via expression level and/or A-to-I editing. We demonstrated that a recoding edit in FLNB (chr3:58156064) inhibits the tumor suppressive activities of the protein to promote growth & invasion. We show that several tumor suppressor microRNAs are also downregulated by ADAR1 to promote cell cycle progression and invasion. This work describes several novel mechanisms of ADAR1-mediated oncogenesis in triple negative breast cancer, providing support to strategies for targeting ADAR1 in this aggressive cancer type with few treatment options.

2022-03-14 | GSE177056 | GEO

Adenosine deaminases that act on RNA induce reproducible changes in abundance and sequence of embryonic miRNAs

Project description:We used transgenic mouse embryos that are deficient in the two enzymatically active RNA editing enzymes ADAR1 and ADAR2 to compare relative frequencies but also sequence composition of mature miRNAs in these genetically modified backgrounds to wild-type mice by Illumina next gen sequencing. Deficiency of ADAR2 leads to a reproducible change in abundance of specific miRNAs and their predicted targets. Changes in miRNA abundance seem unrelated to editing events. Additional deletion of ADAR1 has surprisingly little impact on the mature miRNA repertoire, indicating that miRNA expression is primarily dependent on ADAR2. A to G transitions reflecting A to I editing events can be detected at few sites and at low frequency during the early embryonic stage investigated. Again, most editing events are ADAR2 dependent with only few editing sites being specifically edited by ADAR1. Besides known editing events in miRNAs a few novel, previously unknown editing events were identified. Some editing events are located to the seed region of miRNAs opening the possibility that editing leads to their retargeting. GSM852140-8: sequencing of mature miRNAs of wt, ADAR2-/- and ADAR1-/-/ADAR2-/- female mouse embryos at E11.5 GSM863778-81: Gene expression was measured in wiltype, ADAR2-/- and ADAR1-/-/ADAR2-/- E11.5 whole female mouse embryos using Agilent Whole Mouse Genome Oligo Microarrays 8x60K.

2012-02-02 | E-GEOD-34626 | biostudies-arrayexpress

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