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SPANXA2-OT1 promotes macrophage chemotaxis

ABSTRACT: Coronary artery disease (CAD) remains the leading global cause of death, with macrophages playing a central role in driving inflammation through cytokines, chemokines, and other mediators. Using gene expression meta-analysis and weighted gene co-expression network analysis (WGCNA) of human CAD datasets, we identified 26 lncRNA–mRNA modules and prioritized SPANXA2-OT1 as a key inflammation regulator. Conservation analysis revealed SPANXA2-OT1 to be primate-specific, necessitating human macrophage models derived from PBMCs. IL-1β stimulation induced cytoplasmic SPANXA2-OT1, and antisense oligonucleotide-mediated silencing reduced chemotaxis signatures, validated by RNA-seq and proteomics. Mechanistically, SPANXA2-OT1 directly bound miR-338, as shown by luciferase assays, thereby regulating IL-8 and related chemokines critical for monocyte recruitment. CRISPR/Cas9 deletion of exon 3 further confirmed reduced IL-8 expression and impaired macrophage chemotaxis. Collectively, these findings establish SPANXA2-OT1 as a human-specific regulator of macrophage-driven inflammation in CAD and highlight its promise as a translational biomarker and therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307322 | GEO | 2025/09/09

REPOSITORIES: GEO

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Project description:Coronary artery disease (CAD) remains the leading cause of mortality worldwide. Macrophages play a crucial role in recruiting immune cells and regulating the inflammatory milieu through the release of a diverse array of cytokines, chemokines, and other immune mediators in CAD. Long noncoding RNAs (lncRNAs) interact with DNA, RNA, miRNA, and proteins, making them attractive therapeutic targets for regulating gene expression. Methods and Results: Gene-expression meta-analysis and weighted gene co-expression network analysis (WGCNA) of human CAD datasets identified 26 lncRNA-mRNA co-expression modules. Network prioritization of top co-expression modules identified SPANXA2-OT1 as a potential key candidate. Conservation analysis revealed that SPANXA2-OT1 is human specific and conserved only in primates. We validated the candidate coding-noncoding RNA regulatory triad in human primary macrophages derived from healthy human peripheral blood mononuclear cells (PBMCs). IL-1β induced the expression of SPANXA2-OT1. RNA in situ hybridization localized SPANXA2-OT1 mRNA in cytoplasm of macrophages. Loss-of-function experiments using antisense oligonucleotide (ASO) against SPANXA2-OT1 demonstrated decreased monocyte/macrophage chemotaxis signature after SPANXA2-OT1 silencing, as demonstrated by unbiased global proteomics and RNAseq data. Luciferase assay established that SPANXA2-OT1 binds to miR-338 through its miRNA response elements. Gain-of-function (miR-338 mimic) and loss-of-function (SPANXA2-OT1 ASO) experiments revealed that SPANXA2-OT1-miR-338 axis regulates the expression of monocyte chemotactic genes (e.g., IL-8) that may contribute to the pathophysiology of CAD. CRISPR/Cas9 mediated deletion of the SPANXA2-OT1 functional domain (exon 3, which harbors the miR-338 binding site) in human primary macrophages resulted in decreased IL-8 expression, alteration of the chemokine profile, and decreased macrophage chemotaxis. Conclusion: Our results indicate that the lncRNA SPANXA2-OT1 regulates chemokine signatures and macrophage chemotaxis. One such mechanism involves SPANXA2-OT1 binding to miR-338, making it unavailable to regulate IL-8 expression. Our findings may provide a molecular basis for the future identification of novel biomarkers and therapeutic targets for CAD.

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SPANXA2-OT1 promotes macrophage chemotaxis

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