Abstract
A hallmark of inflammatory diseases is the excessive recruitment and influx of monocytes to sites of tissue damage and their ensuing differentiation into macrophages. Numerous stimuli are known to induce transcriptional changes associated with macrophage phenotype, but posttranscriptional control of human macrophage differentiation is less well understood. Here we show that expression levels of the RNA-binding protein Quaking (QKI) are low in monocytes and early human atherosclerotic lesions, but are abundant in macrophages of advanced plaques. Depletion of QKI protein impairs monocyte adhesion, migration, differentiation into macrophages and foam cell formation in vitro and in vivo. RNA-seq and microarray analysis of human monocyte and macrophage transcriptomes, including those of a unique QKI haploinsufficient patient, reveal striking changes in QKI-dependent messenger RNA levels and splicing of RNA transcripts. The biological importance of these transcripts and requirement for QKI during differentiation illustrates a central role for QKI in posttranscriptionally guiding macrophage identity and function.
Highlights
A hallmark of inflammatory diseases is the excessive recruitment and influx of monocytes to sites of tissue damage and their ensuing differentiation into macrophages
Dynamic changes in gene expression are associated with monocyte to macrophage differentiation, where PU.[1], Signal Transducer and Activator of Transcription (STATs)[9] and CCAAT/Enhancer Binding Protein (C/EBP)s10 are key transcription factors that drive this alteration in cellular phenotype and function[11,12]
We discovered that expression of the RNA-binding proteins (RBPs) Quaking (QKI) is induced in human restenotic lesion-resident vascular smooth muscle cells (VSMCs), where it directly mediates a splicing event in the Myocardin pre-mRNA that governs VSMC function[23]
Summary
A hallmark of inflammatory diseases is the excessive recruitment and influx of monocytes to sites of tissue damage and their ensuing differentiation into macrophages. We discovered that expression of the RBP Quaking (QKI) is induced in human restenotic lesion-resident vascular smooth muscle cells (VSMCs), where it directly mediates a splicing event in the Myocardin pre-mRNA that governs VSMC function[23]. This finding prompted us to investigate whether QKI could serve as an inflammation-sensitive posttranscriptional guide during monocyte to macrophage differentiation. Our studies pinpoint QKI as a dynamic regulator of pre-mRNA splicing and expression profiles that drive monocyte activation, adhesion and differentiation into macrophages, and facilitates their conversion into foam cells
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