Abstract 17619: Deep RNA-Sequencing Uncovers a Broad Species- And Cell-Specific lincRNA Repertoire That Modulates Human Macrophage Activation and Associates With Cardiometabolic Diseases

    loading  Checking for direct PDF access through Ovid

Abstract

Introduction: Sustained and dysfunctional macrophage activation promotes inflammatory cardiometabolic disorders (CMDs), but the role of long non-coding RNAs in human macrophage activation and CMDs is poorly defined.

Objective: We aim to elucidate the long intergenic non-coding RNA (lincRNA) landscape of human macrophages through RNA-sequencing (RNA-seq), genomics and bioinformatics, as well as selective translational and functional studies.

Methods and Results: Using deep RNA-seq and de novo assembly of the lincRNA transcriptome of human monocyte-derived macrophages (HMDM) at resting and stimulated with lipopolysaccharide and interferon-gamma (IFN-γ) for M1-activation, and interleukin-4 for M2-activation, we identified 2,766 macrophage lincRNAs including 861 previously unannotated ones. The majority (~85%) was non-syntenic, or syntenic but not annotated, in the mouse genome. Many macrophage lincRNAs also demonstrated tissue-enriched transcription patterns (21.5%) and enhancer-like chromatin signatures (60.9%). Macrophage activation, particularly to the M1 phenotype, markedly altered the lincRNA expression profiles revealing 96 lincRNAs differentially expressed (fold-change >2 and FDR <0.01), suggesting potential role of many lincRNAs in regulating macrophage inflammatory functions. A subset of macrophage lincRNAs overlapped genome-wide association study loci for CMDs. For example, MacORIS, a syntenic lincRNA not annotated in the mouse genome, harbors variants associated with central obesity. MacORIS is macrophage-enriched and predominantly located in cytoplasm. Knockdown of MacORIS enhanced IFN-γ induced JAK2/STAT1 phosphorylation, suggesting its potential role as a repressor of IFN-γ signaling. Induced pluripotent stem cell-derived macrophages (IPSDM) recapitulated lincRNA transcriptome of primary macrophage and provide a high-fidelity model to study, in particular non-conserved, lincRNAs in human macrophage biology.

Conclusion: In summary, high-resolution transcriptomics identified 100s of lincRNAs that form part of the coordinated response during macrophage activation including specific macrophage lincRNAs associated with human CMDs that modulate macrophage inflammatory functions.

Related Topics

    loading  Loading Related Articles