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 JukemaHilde Van Esch, Ton J. Rabelink, Hilal Kazan, Erik A.L. Biessen, Manuel Ares, Anton Jan Van Zonneveld, Eric P. Van Der Veer

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number10846
JournalNature communications
Volume7
DOIs
StatePublished - Mar 31 2016
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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