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Adenosine-to-Inosine Safeguards Early Human T-cell Lymphopoiesis by Suppressing MDA5-Mediated dsRNA Sensing

ABSTRACT: Steady-state lymphopoiesis from hematopoietic stem and progenitor cells (HSPCs) is critical to maintaining immune competence throughout life. While epigenetic and transcriptional factors governing this process are well reported in both humans and mice, the epitranscriptomic regulation is largely unexplored. In this study, we investigated ADAR1-mediated adenosine-to-inosine (A-to-I) RNA editing during early human T-cell maturation using both human thymic tissues and an artificial thymic organoid (ATO) system. ADAR1 was highly expressed in early T-cell progenitors, and its expression declines as T-cell progenitors progress to the CD4⁺CD8⁺ double-positive (DP) and single-positive (SP) stages. ShRNA-mediated ADAR1 depletion coupled with single-cell RNA sequencing (scRNA-seq) reveals that ADAR1 loss blocks the developmental transition from the Thy2 to Thy3 stage within the CD34⁺ progenitor compartment and leads to the emergence of distinct cell clusters encompassing mixed lineage cells with distinct gene expression patterns marked by global activation of interferon response pathways. Among the dsRNA sensors downstream of A-to-I RNA editing, MDA5 knockdown completely rescues the effects of ADAR1 loss and restores T-cell development. Together, these findings demonstrate dynamic stage-specific ADAR1 regulation and establish its essential role in driving early T-lymphocyte lineage specification through the ADAR1-MDA5 dsRNA-sensing axis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE225778 | GEO | 2026/08/12

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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Adenosine-to-Inosine Safeguards Early Human T-cell Lymphopoiesis by Suppressing MDA5-Mediated dsRNA Sensing

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