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

Ruben G. de Bruin, Lily Shiue, Jurriën Prins, Hetty C. de Boer, Anjana Singh, W. Samuel Fagg, Janine M. van Gils, Jacques M. G. J. Duijs, Sol Katzman, Adriaan O. Kraaijeveld, Stefan Böhringer, Wai Y. Leung, Szymon M. Kielbasa, John P. Donahue, Patrick H.J. van der Zande, Rick Sijbom, Carla M. A. van Alem, Ilze Bot, Cees van Kooten, J. Wouter Jukema, Hilde Van Esch, Ton J. Rabelink, Hilal Kazan, Erik A. L. Biessen, Manuel Ares, Anton Jan van Zonneveld and Eric P. van der Veer ()
Additional contact information
Ruben G. de Bruin: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center
Lily Shiue: Center for Molecular Biology of RNA, Cell and Developmental Biology, University of California
Jurriën Prins: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center
Hetty C. de Boer: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center
Anjana Singh: CARIM, Academic University Hospital Maastricht
W. Samuel Fagg: Center for Molecular Biology of RNA, Cell and Developmental Biology, University of California
Janine M. van Gils: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center
Jacques M. G. J. Duijs: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center
Sol Katzman: Center for Molecular Biology of RNA, Cell and Developmental Biology, University of California
Adriaan O. Kraaijeveld: Leiden University Medical Center
Stefan Böhringer: Leiden University Medical Center
Wai Y. Leung: Leiden University Medical Center
Szymon M. Kielbasa: Leiden University Medical Center
John P. Donahue: Center for Molecular Biology of RNA, Cell and Developmental Biology, University of California
Patrick H.J. van der Zande: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center
Rick Sijbom: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center
Carla M. A. van Alem: Leiden University Medical Center
Ilze Bot: Leiden/Amsterdam Center for Drug Research, Leiden University
Cees van Kooten: Leiden University Medical Center
J. Wouter Jukema: Leiden University Medical Center
Hilde Van Esch: University Hospitals Leuven
Ton J. Rabelink: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center
Hilal Kazan: Antalya International University
Erik A. L. Biessen: CARIM, Academic University Hospital Maastricht
Manuel Ares: Center for Molecular Biology of RNA, Cell and Developmental Biology, University of California
Anton Jan van Zonneveld: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center
Eric P. van der Veer: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center

Nature Communications, 2016, vol. 7, issue 1, 1-20

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10846

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