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A-to-I RNA editing prevents an inflammation-mediated lipodystrophy in adipose tissue

ABSTRACT: RNA editing is a post-transcriptional mechanism that alters the specific nucleotide sequences of RNA to enhance the diversity of gene products. However, the biological function of RNA-editing in different cell types remained poorly understood. In this study, we delineated a comprehensive RNA editome across brown, visceral and subcutaneous adipose tissues from both human and mouse. The edited genes in two species are significantly overlapped and highly enriched for RNA metabolism and lipid metabolism pathways. Using an adipose tissue-specific Adar1 knockout mouse model, we demonstrated that the deficiency of A-to-I editing, through an enhanced formation of double strand RNA (dsRNA) structures, resulted in an inflammation-mediated lipodystrophy which can be fully rescued by deleting Ifih1, a sensor for dsRNA structures. Taken together, our study has addressed a new and fundamental question about the function of RNA editing in adipose tissue.

ORGANISM(S): Mus musculus

PROVIDER: GSE279595 | GEO | 2025/11/28

REPOSITORIES: GEO

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Project description:Mapping the genomic architecture of complex disease has been predicated on the understanding that genetic variants influence disease risk through modifying gene expression. However, recent discoveries have revealed that a significant burden of disease heritability in common autoinflammatory disorders and coronary artery disease is mediated through genetic variation modifying post-transcriptional modification of RNA through adenosine-to-inosine (A-to-I) RNA editing. This common RNA modification is catalyzed by ADAR enzymes, where ADAR1 edits specific immunogenic double stranded RNA (dsRNA) to prevent activation of the double strand RNA (dsRNA) sensor MDA5 (IFIH1) and stimulation of an interferon stimulated gene (ISG) response. Multiple lines of human genetic data indicate impaired RNA editing and increased dsRNA sensing by MDA5 to be an important mechanism of coronary artery disease (CAD) risk. Here, we provide a crucial link between observations in human genetics and mechanistic cell biology leading to progression of CAD. Through analysis of human atherosclerotic plaque, we implicate the vascular smooth muscle cell (SMC) to have a unique requirement for RNA editing, and that ISG induction occurs in SMC phenotypic modulation, implicating MDA5 activation. Through culture of human coronary artery SMCs, generation of a conditional SMC specific Adar1 deletion mouse model on a pro-atherosclerosis background with additional constitutive deletion of MDA5 (Ifih1), and with incorporation of single cell RNA sequencing cellular profiling, we further show that Adar1 controls SMC phenotypic state by regulating Mda5 activation, is required to maintain vascular integrity, and controls progression of atherosclerosis and vascular calcification. Through this work, we describe a fundamental mechanism of CAD, where cell type and context specific RNA editing and sensing of dsRNA mediates disease progression, bridging our understanding of human genetics and disease causality.

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A-to-I RNA editing prevents an inflammation-mediated lipodystrophy in adipose tissue

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