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.
Subject(s)
Macrophages/physiology , Monocytes/physiology , RNA Splicing , RNA-Binding Proteins/physiology , Animals , Atherosclerosis/metabolism , Atherosclerosis/pathology , Cell Differentiation , Foam Cells/cytology , Foam Cells/metabolism , Gene Expression Regulation , Humans , Macrophages/cytology , Macrophages/metabolism , Mice , Models, Biological , Models, Genetic , Monocytes/cytology , Monocytes/metabolism , RNA, Messenger/metabolism , RNA, Messenger/physiology , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolismABSTRACT
Listeners retune the boundaries between phonetic categories to adjust to individual speakers' productions. Lexical information, for example, indicates what an unusual sound is supposed to be, and boundary retuning then enables the speaker's sound to be included in the appropriate auditory phonetic category. In this study, it was investigated whether lexical knowledge that is known to guide the retuning of auditory phonetic categories, can also retune visual phonetic categories. In Experiment 1, exposure to a visual idiosyncrasy in ambiguous audiovisually presented target words in a lexical decision task indeed resulted in retuning of the visual category boundary based on the disambiguating lexical context. In Experiment 2 it was tested whether lexical information retunes visual categories directly, or indirectly through the generalization from retuned auditory phonetic categories. Here, participants were exposed to auditory-only versions of the same ambiguous target words as in Experiment 1. Auditory phonetic categories were retuned by lexical knowledge, but no shifts were observed for the visual phonetic categories. Lexical knowledge can therefore guide retuning of visual phonetic categories, but lexically guided retuning of auditory phonetic categories is not generalized to visual categories. Rather, listeners adjust auditory and visual phonetic categories to talker idiosyncrasies separately.
