Deep RNA Sequencing Uncovers a Repertoire of Human Macrophage Long Intergenic Noncoding RNAs Modulated by Macrophage Activation and Associated With Cardiometabolic Diseases
Year: 2017
Type: article
Abstract: Background Sustained and dysfunctional macrophage activation promotes inflammatory cardiometabolic disorders, but the role of long intergenic noncoding RNA (linc RNA ) in human macrophage activation and cardiometabolic disorders is poorly defined. Through transcriptomics, bioinformatics, and selective functional studies, we sought to elucidate the linc RNA landscape of human macrophages. Methods and Results We used deep RNA sequencing to assemble the linc RNA transcriptome of human monocyte‐derived macrophages at rest and following stimulation with lipopolysaccharide and IFN ‐γ (interferon γ) for M1 activation and IL‐4 (interleukin 4) for M2 activation. Through de novo assembly, we identified 2766 macrophage linc RNA s, including 861 that were previously unannotated. The majority (≈85%) was nonsyntenic or was syntenic but not annotated as expressed in mouse. Many macrophage linc RNA s demonstrated tissue‐enriched transcription patterns (21.5%) and enhancer‐like chromatin signatures (60.9%). Macrophage activation, particularly to the M1 phenotype, markedly altered the linc RNA expression profiles, revealing 96 linc RNA s differentially expressed, suggesting potential roles in regulating macrophage inflammatory functions. A subset of linc RNA s overlapped genomewide association study loci for cardiometabolic disorders. Mac ORIS (macrophage‐enriched obesity‐associated lincRNA serving as a repressor of IFN‐γ signaling), a macrophage‐enriched linc RNA not expressed in mouse macrophages, harbors variants associated with central obesity. Knockdown of Mac ORIS , which is located in the cytoplasm, enhanced IFN ‐γ–induced JAK 2 (Janus kinase 2) and STAT 1 (signal transducer and activator of transcription 1) phosphorylation in THP ‐1 macrophages, suggesting a potential role as a repressor of IFN ‐γ signaling. Induced pluripotent stem cell–derived macrophages recapitulated the linc RNA transcriptome of human monocyte‐derived macrophages and provided a high‐fidelity model with which to study linc RNA s in human macrophage biology, particularly those not conserved in mouse. Conclusions High‐resolution transcriptomics identified linc RNA s that form part of the coordinated response during macrophage activation, including specific macrophage linc RNA s associated with human cardiometabolic disorders that modulate macrophage inflammatory functions.
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,810
Funders: National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: iPS-derived hepatocytes for interrogation of lipid phenotypes, Human LincRNAs in Macrophage Biology and Related Cardiometabolic Diseases, Elucidation of Tissue-Specific Transcriptomic Profiles in Cardio-metabolic Disease, Becton Dickinson LSR II Analytical Flow Cytometer, Macrophage-specific function of GWAS CAD-associated LIPA alleles in atherosclerosis, Statistical Methods for Transcriptome Profiling Using RNA Sequencing, Training in Renal Research, Institutional Career Development Core, Cancer Center Support Grant
OpenAlex ID: W2768429801