Abstract 217: Quaking Post-Transcriptionally Guides Monocyte Adhesion and Differentiation into the Pro-Inflammatory Macrophage
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 new transcription necessary for macrophage identity, but post-transcriptional control of human macrophage differentiation is less well understood. Here, we detail our discovery that levels of the RNA-binding protein Quaking (QKI) are low in monocytes of early atherosclerotic lesions, but abundant in macrophages of advanced plaques. Specific depletion of QKI protein impaired monocyte adhesion, migration and differentiation into macrophages, and lesion formation. RNA-seq and microarray analysis of human monocyte and macrophage transcriptomes, including those of a unique QKI haploinsufficient patient, reveal developmental changes in RNA levels and alternative splicing of RNA transcripts enriched in QKI-bound sequence elements. The importance of these transcripts and requirement for QKI during differentiation illustrates a central role for QKI in post-transcriptionally guiding macrophage identity and function. These studies implicate QKI as a novel target for therapeutic intervention in inflammatory diseases.
Author Disclosures: R.G. de Bruin: None. L. Shiue: None. A. Djarmshi: None. H.C. de Boer: None. W. Leung: None. J.M. van Gils: None. J. Prins: None. J.M.G. Duijs: None. P.H.J. van der Zande: None. T.J. Rabelink: None. W.J. Jukema: None. H. van Esch: None. H. Kazan: None. E.A.L. Biessen: None. M. Ares: None. A. van Zonneveld: None. E.P. van der Veer: None.
- © 2015 by American Heart Association, Inc.