Deep RNA Sequencing Uncovers a Repertoire of Human Macrophage Long Intergenic Noncoding RNAs Modulated by Macrophage Activation and Associated With Cardiometabolic Diseases

作者：Zhang Hanrui; Xue Chenyi; Wang Ying; Shi Jianting; Zhang Xuan; Li Wenjun; Nunez Sara; Foulkes Andrea S; Lin Jennie; Hinkle Christine C; Yang Wenli; Morrisey Edward E; Rader Daniel J; Li Mingyao; Reilly Muredach P

来源：Journal of the American Heart Association, 2017, 6(11): e007431.

DOI：10.1161/JAHA.117.007431

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<jats:title>Background</jats:title>
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Sustained and dysfunctional macrophage activation promotes inflammatory cardiometabolic disorders, but the role of long intergenic noncoding
<jats:styled-content style="fixed-case">RNA</jats:styled-content>
(linc
<jats:styled-content style="fixed-case">RNA</jats:styled-content>
) in human macrophage activation and cardiometabolic disorders is poorly defined. Through transcriptomics, bioinformatics, and selective functional studies, we sought to elucidate the linc
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landscape of human macrophages.
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<jats:title>Methods and Results</jats:title>
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We used deep
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sequencing to assemble the linc
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transcriptome of human monocyte‐derived macrophages at rest and following stimulation with lipopolysaccharide and
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‐γ (interferon γ) for M1 activation and IL‐4 (interleukin 4) for M2 activation. Through de novo assembly, we identified 2766 macrophage linc
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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
<jats:styled-content style="fixed-case">RNA</jats:styled-content>
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
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expression profiles, revealing 96 linc
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s differentially expressed, suggesting potential roles in regulating macrophage inflammatory functions. A subset of linc
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s overlapped genomewide association study loci for cardiometabolic disorders. Mac
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(macrophage‐enriched obesity‐associated lincRNA serving as a repressor of IFN‐γ signaling), a macrophage‐enriched linc
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not expressed in mouse macrophages, harbors variants associated with central obesity. Knockdown of Mac
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<jats:italic>,</jats:italic>
which is located in the cytoplasm, enhanced
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‐γ–induced
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2 (Janus kinase 2) and
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1 (signal transducer and activator of transcription 1) phosphorylation in
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‐1 macrophages, suggesting a potential role as a repressor of
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‐γ signaling. Induced pluripotent stem cell–derived macrophages recapitulated the linc
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transcriptome of human monocyte‐derived macrophages and provided a high‐fidelity model with which to study linc
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s in human macrophage biology, particularly those not conserved in mouse.
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<jats:title>Conclusions</jats:title>
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High‐resolution transcriptomics identified linc
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s that form part of the coordinated response during macrophage activation, including specific macrophage linc
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s associated with human cardiometabolic disorders that modulate macrophage inflammatory functions.
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• 出版日期2017-11