Journal Article

Quaking promotes monocyte differentiation into pro-atherogenic macrophages by controlling pre-mRNA splicing and gene expression

Duijs, Jacques M. G. J., van Gils, Janine M., Böhringer, Stefan, de Bruin, Ruben G., Shiue, Lily, van Kooten, Cees, Jukema, J. Wouter, Leung, Wai Y., Rabelink, Ton J., Ares Jr, Manuel, Fagg, W. Samuel, Biessen, Erik A. L., Sijbom, Rick, Singh, Anjana, van der Zande, Patrick H.J., Bot, Ilze, Kielbasa, Szymon M., de Boer, Hetty C., Van Esch, Hilde, Prins, Jurriën, van der Veer, Eric P., Kazan, Hilal, van Alem, Carla M. A., Donahue, John P., van Zonneveld, Anton Jan, Kraaijeveld, Adriaan O., Katzman, Sol

2016

Overview

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. Post-transcriptional control of RNA is important in health and disease. Here, the authors show that the RNA-binding protein Quaking guides pre-mRNA splicing and transcript abundance during monocyte to macrophage differentiation, and that Quaking depletion impairs pro-atherogenic foam cell formation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 38/39 / 631/208/199 / 631/250/2504/342 / 631/337/1645/1792 / 631/45/612/1230 / 64 / 64/60 / 82 / 82/51 / Animals / Atherosclerosis / Atherosclerosis - metabolism / Atherosclerosis - pathology / Biology / Cell Differentiation / Foam Cells - cytology / Foam Cells - metabolism / Gene expression / Gene Expression Regulation / Humanities and Social Sciences / Humans / Localization / Macrophages - cytology / Macrophages - metabolism / Macrophages - physiology / Mice / MicroRNAs / Models, Biological / Models, Genetic / Monocytes - cytology / Monocytes - metabolism / Monocytes - physiology / multidisciplinary / Protein expression / Proteins / RNA Splicing / RNA, Messenger - metabolism / RNA, Messenger - physiology / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / RNA-Binding Proteins - physiology / Science / Science (multidisciplinary) / Transcription factors