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RNA-sequencing of brain RNA from mice with compound mutations in ADAR1 and MAVS or ZBP1

ABSTRACT: The purpose of this study was to examine the role of MAVS and ZBP1 in the phenotype that develops when ADAR1 activity is missing, in particular when the Za domain of ADAR1 is mutated. Mice homozygous for a Za domain-mutant allele of Adar1 (Adar1mZa/mZa mice) were compared with control mice carrying one mZa allele and one wild type allele of Adar1 (Adar1wt/mZa mice) and with mice carrying one mZa and one null Adar1 allele (Adar1-/mZa mice). Adar1-/mZa mice were also compared with mice additionally deficient in ZBP1 (Adar1-/mZa Zbp1-/- mice) or MAVS (Adar1-/mZa Mavs-/- mice). Given the early postnatal lethal phenotype that develops in Adar1-/mZa mice, comparisons were made in RNA isolated from brain tissue from newborn mice of each genotype (4 mice per genotype).

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Mus musculus

SUBMITTER: George Kassiotis

PROVIDER: E-MTAB-11537 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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RNA-sequencing of lung RNA from mice with compound mutations in ADAR1 and MAVS, ZBP1 or RIPK3.

Project description:The purpose of this study was to examine the role of MAVS, ZBP1 and RIPK3 in the phenotype that develops when ADAR1 activity is impaired, in particular when the Za domain of ADAR1 is mutated. Mice homozygous for a Za domain-mutant allele of Adar1 (Adar1mZa/mZa mice) and mice carrying one mZa and one null Adar1 allele (Adar1-/mZa mice) were compared with control mice that were either wild type or heterozygous for the Adar1 mZa allele (Adar1wt/mZa mice). The effects of MAVS deficiency, RIPK3 deficiency, ZBP1 deficiency or ZBP1 Za domain mutations were assessed by analysing compound mutant mice. Given the early postnatal lethal phenotype that develops in Adar1-/mZa mice, comparisons were made in RNA isolated from lung tissue from newborn mice of each genotype (5 mice per genotype). As Adar1-/mZa mice additionally lacking Mavs or Zbp1 are viable, adult mice (15-20 weeks of age) were also used for several compound mutations as donors of lung tissue.

2022-06-09 | E-MTAB-11540 | biostudies-arrayexpress

RNA-sequencing of splenic RNA from mice with compound mutations in ADAR1 and ZBP1

Project description:The purpose of this study was to examine the role of ZBP1 in the phenotype that develops when ADAR1 activity is missing, in particular when the Zα domain of ADAR1 is mutated. Mice homozygous for a Zα domain-mutant allele of Adar1 (Adar1mZα/mZα mice) were compared with control mice carrying one mZα allele and one wild type allele of Adar1 (Adar1wt/mZα mice) and with mice carrying one mZα and one null Adar1 allele (Adar1-/mZα mice). Adar1-/mZα mice were also compared with mice additionally deficient in ZBP1 (Adar1-/mZα Zbp1-/- mice). Given the early postnatal lethal phenotype that develops in Adar1-/mZα mice, comparisons were made in RNA isolated from spleen tissue from newborn mice of each genotype (5 mice per genotype).

2022-04-27 | E-MTAB-10953 | biostudies-arrayexpress

RNA-sequencing of brain RNA from mice with compound mutations in ADAR1 and MAVS or ZBP1

Project description:RNA-sequencing of brain RNA from mice with compound mutations in ADAR1 and MAVS or ZBP1

| PRJEB51557 | ENA

ADAR1 restricts ZBP1–mediated immune response and PANoptosis to promote tumorigenesis

Project description:Cell death provides host defense and maintains homeostasis. Zα-containing molecules are essential for these processes. ZBP1 activates inflammatory cell death, PANoptosis, while ADAR1 serves as an RNA editor to maintain homeostasis. Here, we identify and characterize ADAR1’s interaction with ZBP1, defining its role in cell death regulation and tumorigenesis. Combining IFNs and nuclear export inhibitors (NEIs) activates ZBP1–dependent PANoptosis. ADAR1 suppresses PANoptosis by interacting with the Zα2 domain of ZBP1 to limit ZBP1 and RIPK3 interactions. Adar1fl/flLysMcre mice are resistant to development of colorectal cancer and melanoma, but deletion of the ZBP1 Zα2 domain restores tumorigenesis in these mice. In addition, treating wildtype mice with IFN-γ and the NEI KPT-330 regresses melanoma in a ZBP1–dependent manner. Our findings suggest that ADAR1 suppresses ZBP1–mediated PANoptosis, promoting tumorigenesis. Defining the functions of ADAR1 and ZBP1 in cell death is fundamental to inform therapeutic strategies for cancer and other diseases.

2021-10-19 | GSE184323 | GEO

RNA-sequencing of lung RNA from mice with compound mutations in ADAR1 and MAVS, ZBP1 or RIPK3.

Project description:RNA-sequencing of lung RNA from mice with compound mutations in ADAR1 and MAVS, ZBP1 or RIPK3.

| PRJEB51613 | ENA

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 mutation causes ZBP1-dependent immunopathology I

Project description:The RNA editing enzyme ADAR1 is essential for suppression of innate immune activation and pathology caused by aberrant recognition of self-RNA, a role it carries out by disrupting the duplex structure of endogenous double-stranded RNA species. A point mutation in the Z-nucleic-acid binding domain (ZBD) of ADAR1 is associated with severe autoinflammatory disease. ZBP1 is the only other ZBD-containing mammalian protein and its activation can trigger both cell death and transcriptional responses via the kinases RIPK1 and RIPK3, and the protease caspase-8. Here, we show that the pathology caused by ADAR1 ZBD mutation is driven by activation of ZBP1. We found that ablation of ZBP1 fully rescued the overt pathology caused by ADAR1 mutation, without reversing the underlying inflammatory program caused by this mutation. While loss of RIPK3 partially phenocopied the protective effects of ZBP1 ablation, combined deletion of caspase-8 and RIPK3, or of caspase-8 and MLKL, unexpectedly exacerbated the pathogenic effects of ADAR1 mutation. These findings indicate that ADAR1 is a negative regulator of sterile ZBP1 activation, and that ZBP1-dependent signaling underlies the autoinflammatory pathology caused by mutation of ADAR1.

2022-08-10 | GSE200985 | GEO

ADAR1 mutation causes ZBP1-dependent immunopathology

2022-06-11 | GSE200854 | GEO

ADAR1 mutation causes ZBP1-dependent immunopathology II

2022-08-10 | GSE200986 | GEO

RNA editing modulates pathways critical to B cell lymphomagenesis

Project description:Diffuse large B cell lymphoma (DLBCL) is one of the most common and aggressive types of B cell lymphoma. Subtype heterogeneity cannot be completely explained by genomic alterations and/or gene expression differences, suggesting that additional mechanisms are involved. Here, we explore the contribution of an epitranscriptomic modification to B cell lymphomagenesis. Our data demonstrate that ADAR1-mediated RNA editing (deamination of adenosine to inosine) targets novel candidate driver genes within well-known disease-associated pathways in DLBCL. Within these pathways, DNA mutations and RNA editing events are often mutually exclusive at the gene level, suggesting that tumours can modulate pathway outcomes by altering sequence at either the genomic or the transcriptomic level. In contrast to what has been found in solid tumours, in DLBCL low ADAR1 expression correlates with low interferon-stimulated gene (ISG) scores and with a microenvironment that is not inflamed. To investigate the molecular mechanism behind the inability of DLBCL to mount an ISG response upon loss of ADAR1, we focused on one candidate MAVS, a central regulator of ISG (as well as NFkB) signaling. MAVS is never mutated but robustly edited by ADAR1 at its 3’UTR, and editing correlates with increased MAVS protein levels and increased downstream activation of the ISG as well as NFkB pathways. Using targeted base editing tools to specifically restore MAVS editing in ADAR1-deficient cells, we demonstrate that MAVS editing is directly causal to an increase in expression of genes downstream this signaling pathway. Our data imply that DLBCL tumours edit MAVS to strengthen NFkB signaling, to which they are dependent on survival; thus, targeted loss of MAVS editing might sensitize tumours to cell death. Overall, ADAR1-mediated RNA editing represents a new tumour evasion mechanism underlying DLBCL lymphomagenesis, with features distinct from those derived from solid tumours to date.

2022-09-01 | GSE145011 | GEO

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