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Transcriptome-wide regulation of pre-mRNA splicing and expression by the RNA-binding protein Quaking during monocyte to macrophage differentiation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE74979 | GEO | 2016/01/04

SECONDARY ACCESSION(S): PRJNA302113

REPOSITORIES: GEO

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Transcriptome-wide regulation of pre-mRNA splicing and expression by the RNA-binding protein Quaking during monocyte to macrophage differentiation

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-01-04 | E-GEOD-74979 | biostudies-arrayexpress

Transcriptome-wide regulation of pre-mRNA splicing and expression by the RNA-binding protein Quaking during monocyte to macrophage differentiation [Microarray]

Project description:Expression levels of the RNA-binding protein Quaking (QKI) are low in monocytes of early, human atherosclerotic lesions, but abundant in macrophages of advanced plaques. Specific depletion of QKI protein impaired 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, revealed striking changes in QKI-dependent mRNA levels and splicing of RNA transcripts. Microarray analysis of gene expression and splicing in THP-1 cells transfected with shRNAs, with or without PMA treatment to induce differentiation. 12 total samples were analyzed: THP-1 monocytic cell line transfected with QKI or control shRNAs; samples taken at day 0 or day 3 of PMA-induced differentiation into macrophages.

2016-01-04 | E-GEOD-74887 | biostudies-arrayexpress

Transcriptome-wide regulation of pre-mRNA splicing and expression by the RNA-binding protein Quaking during monocyte to macrophage differentiation [RNA-Seq]

Project description:Expression levels of the RNA-binding protein Quaking (QKI) are low in monocytes of early, human atherosclerotic lesions, but abundant in macrophages of advanced plaques. Specific depletion of QKI protein impaired 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, revealed striking changes in QKI-dependent mRNA levels and splicing of RNA transcripts. RNA-seq analysis of primary monocytes and macrophages from a QKI haploinsufficient patient and their (control) sibling.

2016-01-04 | E-GEOD-74978 | biostudies-arrayexpress

Transcriptome-wide regulation of pre-mRNA splicing and expression by the RNA-binding protein Quaking during monocyte to macrophage differentiation [Microarray]

2016-01-04 | GSE74887 | GEO

Transcriptome-wide regulation of pre-mRNA splicing and expression by the RNA-binding protein Quaking during monocyte to macrophage differentiation [RNA-Seq]

2016-01-04 | GSE74978 | GEO

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

Project 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.

| S-EPMC4821877 | biostudies-literature

Comprehensive analysis of neuronal guidance cue expression regulation during monocyte-to-macrophage differentiation reveals post-transcriptional regulation of semaphorin7A by the RNA-binding protein quaking.

Project description:In response to inflammatory cytokines and chemokines, monocytes differentiate into macrophages. Comprehensive analysis of gene expression regulation of neuronal guidance cue (NGC) ligands and receptors in the monocyte-to-macrophage differentiation process is not available yet. We performed transcriptome profiling in both human primary PBMCs/PBMC-derived macrophages and THP-1 cells/THP-1-macrophages using microarray or RNA sequencing methods. Pathway analysis showed that the axonal guidance pathway is significantly regulated upon monocyte differentiation. We confirmed NGC ligands and receptors which were consistently regulated, including SEMA4D, SEMA7A, NRP1, NRP2, PLXNA1 and PLXNA3. The involvement of RNA-binding protein quaking (QKI) in the regulation of NGC expression was investigated using monocytes and macrophages from a QKI haplo-insufficient patient and her healthy sibling. This revealed a positive correlation of SEMA7A expression with QKI expression. In silico analysis of 3'UTRs of NGCs proposed the competitive binding of QKI to proximal microRNA targeting sites as the mechanism of QKI-dependent regulation of SEMA7A. RNA immunoprecipitation confirmed an interaction of QKI with the 3'UTR of SEMA7A. Loss of SEMA7A resulted in monocyte differentiation towards a more anti-inflammatory macrophage. Taken together, the axonal guidance pathway is regulated during monocyte-to-macrophage differentiation, and the regulation is in line with the necessary functional adaption for the specialised role of macrophages.

| S-EPMC7882812 | biostudies-literature

Transcriptome-wide regulation of pre-mRNA splicing and expression by the RNA-binding protein Quaking during monocyte to macrophage differentiation

Project description:Transcriptome-wide regulation of pre-mRNA splicing and expression by the RNA-binding protein Quaking during monocyte to macrophage differentiation

| PRJNA302113 | ENA

RNA-binding Protein Quaking Stabilizes Sirt2 mRNA during Oligodendroglial Differentiation.

Project description:Myelination is controlled by timely expression of genes involved in the differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes (OLs). Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase, plays a critical role in OL differentiation by promoting both arborization and downstream expression of myelin-specific genes. However, the mechanisms involved in regulating SIRT2 expression during OL development are largely unknown. The RNA-binding protein quaking (QKI) plays an important role in myelination by post-transcriptionally regulating the expression of several myelin specific genes. In quaking viable (qkv/qkv ) mutant mice, SIRT2 protein is severely reduced; however, it is not known whether these genes interact to regulate OL differentiation. Here, we report for the first time that QKI directly binds to Sirt2 mRNA via a common quaking response element (QRE) located in the 3' untranslated region (UTR) to control SIRT2 expression in OL lineage cells. This interaction is associated with increased stability and longer half-lives of Sirt2.1 and Sirt2.2 transcripts leading to increased accumulation of Sirt2 transcripts. Consistent with this, overexpression of qkI promoted the expression of Sirt2 mRNA and protein. However, overexpression of the nuclear isoform qkI-5 promoted the expression of Sirt2 mRNA, but not SIRT2 protein, and delayed OL differentiation. These results suggest that the balance in the subcellular distribution and temporal expression of QKI isoforms control the availability of Sirt2 mRNA for translation. Collectively, our study demonstrates that QKI directly plays a crucial role in the post-transcriptional regulation and expression of Sirt2 to facilitate OL differentiation.

| S-EPMC5392665 | biostudies-literature

Autogenous cross-regulation of Quaking mRNA processing and translation balances Quaking functions in splicing and translation.

Project description:Quaking protein isoforms arise from a single Quaking gene and bind the same RNA motif to regulate splicing, translation, decay, and localization of a large set of RNAs. However, the mechanisms by which Quaking expression is controlled to ensure that appropriate amounts of each isoform are available for such disparate gene expression processes are unknown. Here we explore how levels of two isoforms, nuclear Quaking-5 (Qk5) and cytoplasmic Qk6, are regulated in mouse myoblasts. We found that Qk5 and Qk6 proteins have distinct functions in splicing and translation, respectively, enforced through differential subcellular localization. We show that Qk5 and Qk6 regulate distinct target mRNAs in the cell and act in distinct ways on their own and each other's transcripts to create a network of autoregulatory and cross-regulatory feedback controls. Morpholino-mediated inhibition of Qk translation confirms that Qk5 controls Qk RNA levels by promoting accumulation and alternative splicing of Qk RNA, whereas Qk6 promotes its own translation while repressing Qk5. This Qk isoform cross-regulatory network responds to additional cell type and developmental controls to generate a spectrum of Qk5/Qk6 ratios, where they likely contribute to the wide range of functions of Quaking in development and cancer.

| S-EPMC5695090 | biostudies-literature

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