title: Quaking promotes monocyte differentiation into pro-atherogenic macrophages by controlling pre-mRNA splicing and gene expression.
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.
authors.affiliation: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.|Department of Internal Medicine (Nephrology), Leiden University Medical Center, Albinusdreef 2, C7-36, PO Box 9600, 2300RC, Leiden The Netherlands.
authors.forename: Ruben G
authors.initials: RG
authors.lastname: de Bruin
authors.affiliation: Center for Molecular Biology of RNA, Department of Molecular, Cell and Developmental Biology, University of California, 1156 High Street, Santa Cruz, California 95064, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Shiue
authors.affiliation: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.|Department of Internal Medicine (Nephrology), Leiden University Medical Center, Albinusdreef 2, C7-36, PO Box 9600, 2300RC, Leiden The Netherlands.
authors.forename: Jurriën
authors.initials: J
authors.lastname: Prins
authors.affiliation: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.|Department of Internal Medicine (Nephrology), Leiden University Medical Center, Albinusdreef 2, C7-36, PO Box 9600, 2300RC, Leiden The Netherlands.
authors.forename: Hetty C
authors.initials: HC
authors.lastname: de Boer
authors.affiliation: Department of Pathology, CARIM, Academic University Hospital Maastricht, P. Debyelaan 25, 6229HX Maastricht, The Netherlands.
authors.forename: Anjana
authors.initials: A
authors.lastname: Singh
authors.affiliation: Center for Molecular Biology of RNA, Department of Molecular, Cell and Developmental Biology, University of California, 1156 High Street, Santa Cruz, California 95064, USA.
authors.forename: W Samuel
authors.initials: WS
authors.lastname: Fagg
authors.affiliation: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.|Department of Internal Medicine (Nephrology), Leiden University Medical Center, Albinusdreef 2, C7-36, PO Box 9600, 2300RC, Leiden The Netherlands.
authors.forename: Janine M
authors.initials: JM
authors.lastname: van Gils
authors.affiliation: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.|Department of Internal Medicine (Nephrology), Leiden University Medical Center, Albinusdreef 2, C7-36, PO Box 9600, 2300RC, Leiden The Netherlands.
authors.forename: Jacques M G J
authors.initials: JM
authors.lastname: Duijs
authors.affiliation: Center for Molecular Biology of RNA, Department of Molecular, Cell and Developmental Biology, University of California, 1156 High Street, Santa Cruz, California 95064, USA.
authors.forename: Sol
authors.initials: S
authors.lastname: Katzman
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.
authors.forename: Adriaan O
authors.initials: AO
authors.lastname: Kraaijeveld
authors.affiliation: Department of Medical Biostatistics, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Böhringer
authors.affiliation: Department of Sequencing Analysis Support Core, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.
authors.forename: Wai Y
authors.identifier: http://orcid.org/0000-0003-1041-1885
authors.initials: WY
authors.lastname: Leung
authors.affiliation: Department of Medical Biostatistics, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.
authors.forename: Szymon M
authors.initials: SM
authors.lastname: Kielbasa
authors.affiliation: Center for Molecular Biology of RNA, Department of Molecular, Cell and Developmental Biology, University of California, 1156 High Street, Santa Cruz, California 95064, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Donahue
authors.affiliation: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.|Department of Internal Medicine (Nephrology), Leiden University Medical Center, Albinusdreef 2, C7-36, PO Box 9600, 2300RC, Leiden The Netherlands.
authors.forename: Patrick H J
authors.initials: PH
authors.lastname: van der Zande
authors.affiliation: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.|Department of Internal Medicine (Nephrology), Leiden University Medical Center, Albinusdreef 2, C7-36, PO Box 9600, 2300RC, Leiden The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Sijbom
authors.affiliation: Department of Internal Medicine (Nephrology), Leiden University Medical Center, Albinusdreef 2, C7-36, PO Box 9600, 2300RC, Leiden The Netherlands.
authors.forename: Carla M A
authors.initials: CM
authors.lastname: van Alem
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, 2333CC Leiden, The Netherlands.
authors.forename: Ilze
authors.identifier: http://orcid.org/0000-0002-1242-1959
authors.initials: I
authors.lastname: Bot
authors.affiliation: Department of Internal Medicine (Nephrology), Leiden University Medical Center, Albinusdreef 2, C7-36, PO Box 9600, 2300RC, Leiden The Netherlands.
authors.forename: Cees
authors.initials: C
authors.lastname: van Kooten
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.|Durrer Center for Cardiogenetic Research, Meiburgdreef 9, 1105AZ Amsterdam, The Netherlands.
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.affiliation: Department of Human Genetics, University Hospitals Leuven, Herestraat 43, 3000 Leuven, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.affiliation: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.|Department of Internal Medicine (Nephrology), Leiden University Medical Center, Albinusdreef 2, C7-36, PO Box 9600, 2300RC, Leiden The Netherlands.
authors.forename: Ton J
authors.initials: TJ
authors.lastname: Rabelink
authors.affiliation: Department of Computer Engineering, Antalya International University, Universit Cad. No.2, Antalya 07190, Turkey.
authors.forename: Hilal
authors.initials: H
authors.lastname: Kazan
authors.affiliation: Department of Pathology, CARIM, Academic University Hospital Maastricht, P. Debyelaan 25, 6229HX Maastricht, The Netherlands.|Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, 2333CC Leiden, The Netherlands.
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
authors.affiliation: Center for Molecular Biology of RNA, Department of Molecular, Cell and Developmental Biology, University of California, 1156 High Street, Santa Cruz, California 95064, USA.
authors.forename: Manuel
authors.identifier: http://orcid.org/0000-0002-2552-9168
authors.initials: M
authors.lastname: Ares
authors.affiliation: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.|Department of Internal Medicine (Nephrology), Leiden University Medical Center, Albinusdreef 2, C7-36, PO Box 9600, 2300RC, Leiden The Netherlands.
authors.forename: Anton Jan
authors.initials: AJ
authors.lastname: van Zonneveld
authors.affiliation: Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands.|Department of Internal Medicine (Nephrology), Leiden University Medical Center, Albinusdreef 2, C7-36, PO Box 9600, 2300RC, Leiden The Netherlands.
authors.forename: Eric P
authors.initials: EP
authors.lastname: van der Veer
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D005487:Foam Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D008957:Models, Genetic; D009000:Monocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism / Q000502:physiology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C490832:QKI protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins