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ADAR1-Dependent RNA Editing Promotes MET and iPSC Reprogramming by Alleviating ER Stress

ABSTRACT: In contrast to chromatin and DNA modifications, whose roles has been widely investigated, the contribution of RNA epitranscriptomics to specification of cellular identity remains largely unexplored. In this study we demonstrated that loss-of-function of ADAR1, an enzyme that catalyzes adenosine deamination in RNA, abrogates epithelial cell fate acquisition during somatic cell reprogramming. Our findings indicate that absence of A-to-I editing triggers innate immune response and endoplasmic reticulum stress by the cytoplasmic sensor MDA5, resulting in reduced Mesenchymal-to-Epithelial Transition (MET). Additionally, ADAR1 catalytic activity regulates the subcellular distribution of double-strand containing RNAs encoding protein-related membranes. Our study uncovers for the first time the implication of A-to-I RNA editing in cellular plasticity and epithelial specification.

ORGANISM(S): Mus musculus

PROVIDER: GSE130310 | GEO | 2020/05/09

REPOSITORIES: GEO

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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

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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.

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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 (Adult Brain)]

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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)]

2017-08-14 | GSE94388 | GEO

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

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

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2014-12-19 | E-GEOD-62917 | biostudies-arrayexpress

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