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Published January 1, 2016 | Version v1
Journal article Open

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

Creators

  • 1. Univ Calif Santa Cruz, Ctr Mol Biol RNA, Dept Mol Cell & Dev Biol, 1156 High St, Santa Cruz, CA 95064 USA
  • 2. Acad Univ Hosp Maastricht, Dept Pathol, CARIM, P Debyelaan 25, NL-6229 HX Maastricht, Netherlands
  • 3. Leiden Univ, Med Ctr, Dept Cardiol, Albinusdreef 2, NL-2300 RC Leiden, Netherlands
  • 4. Leiden Univ, Dept Med Biostat, Med Ctr, Albinusdreef 2, NL-2300 RC Leiden, Netherlands
  • 5. Leiden Univ, Dept Sequencing Anal Support Core, Med Ctr, Albinusdreef 2, NL-2300 RC Leiden, Netherlands
  • 6. Leiden Univ, Med Ctr, Dept Internal Med Nephrol, Albinusdreef 2,C7-36,POB 9600, NL-2300 RC Leiden, Netherlands
  • 7. Leiden Univ, Leiden Amsterdam Ctr Drug Res, Div Biopharmaceut, Einsteinweg 55, NL-2333 CC Leiden, Netherlands

Description

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.

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