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

  • Nat Commun. 2016 Mar 31:7:10846. doi: 10.1038/ncomms10846.
Ruben G de Bruin  1  2 ,  Lily Shiue  3 ,  Jurriën Prins  1  2 ,  Hetty C de Boer  1  2 ,  Anjana Singh  4 ,  W Samuel Fagg  3 ,  Janine M van Gils  1  2 ,  Jacques M G J Duijs  1  2 ,  Sol Katzman  3 ,  Adriaan O Kraaijeveld  5 ,  Stefan Böhringer  6 ,  Wai Y Leung  7 ,  Szymon M Kielbasa  6 ,  John P Donahue  3 ,  Patrick H J van der Zande  1  2 ,  Rick Sijbom  1  2 ,  Carla M A van Alem  2 ,  Ilze Bot  8 ,  Cees van Kooten  2 ,  J Wouter Jukema  5  9 ,  Hilde Van Esch  10 ,  Ton J Rabelink  1  2 ,  Hilal Kazan  11 ,  Erik A L Biessen  4  8 ,  Manuel Ares Jr  3 ,  Anton Jan van Zonneveld  1  2 ,  Eric P van der Veer  1  2
Affiliations
  • 1. Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.
  • 2. Department of Internal Medicine (Nephrology), Leiden University Medical Center, Albinusdreef 2, C7-36, PO Box 9600, 2300RC, Leiden The Netherlands.
  • 3. Center for Molecular Biology of RNA, Department of Molecular, Cell and Developmental Biology, University of California, 1156 High Street, Santa Cruz, California 95064, USA.
  • 4. Department of Pathology, CARIM, Academic University Hospital Maastricht, P. Debyelaan 25, 6229HX Maastricht, The Netherlands.
  • 5. Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.
  • 6. Department of Medical Biostatistics, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.
  • 7. Department of Sequencing Analysis Support Core, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.
  • 8. Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, 2333CC Leiden, The Netherlands.
  • 9. Durrer Center for Cardiogenetic Research, Meiburgdreef 9, 1105AZ Amsterdam, The Netherlands.
  • 10. Department of Human Genetics, University Hospitals Leuven, Herestraat 43, 3000 Leuven, Belgium.
  • 11. Department of Computer Engineering, Antalya International University, Universit Cad. No.2, Antalya 07190, Turkey.
PMID: 27029405 DOI: 10.1038/ncomms10846
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.