Transcriptome-wide regulation of pre-mRNA splicing and expression by the RNA-binding protein Quaking during monocyte to macrophage differentiation
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Lily Shiue
PROVIDER: E-GEOD-74979 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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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
Project description:Macrophages play a critical role in innate immunity, and the expression of early response genes orchestrate much of the initial response of the immune system. Macrophages undergo extensive transcriptional reprogramming in response to inflammatory stimuli such as Lipopolysaccharide (LPS). To identify gene transcription regulation patterns involved in early innate immune responses, we used two genome-wide approaches - gene expression profiling and chromatin immunoprecipitation-sequencing (ChIP-seq) analysis. We examined the effect of 2 hrs LPS stimulation on early gene expression and its relation to chromatin remodeling (H3 acetylation; H3Ac) and promoter binding of Sp1 and RNA polymerase II phosphorylated at serine 5 (S5P RNAPII), which is a marker for transcriptional initiation. Our results indicate novel and alternative gene regulatory mechanisms for certain proinflammatory genes. We identified two groups of up-regulated inflammatory genes with respect to chromatin modification and promoter features. One group, including highly up-regulated genes such as tumor necrosis factor (TNF), was characterized by H3Ac, high CpG content and lack of TATA boxes. The second group, containing inflammatory mediators (interleukins and CCL chemokines), was up-regulated upon LPS stimulation despite lacking H3Ac in their annotated promoters, which were low in CpG content but did contain TATA boxes. Genome-wide analysis showed that few H3Ac peaks were unique to either +/-LPS condition. However, within these, an unpacking/expansion of already existing H3Ac peaks was observed upon LPS stimulation. In contrast, a significant proportion of S5P RNAPII peaks (approx 40%) was unique to either condition. Furthermore, data indicated a large portion of previously unannotated TSSs, particularly in LPS-stimulated macrophages, where only 28% of unique S5P RNAPII peaks overlap annotated promoters. The regulation of the inflammatory response appears to occur in a very specific manner at the chromatin level for specific genes and this study highlights the level of fine-tuning that occurs in the immune response. 4 pairs of THP-1 cells either stimulated with LPS or not This submission represents transcriptome component of study.
2012-03-07 | E-GEOD-32141 | biostudies-arrayexpress
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
Project description:Background: Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide, most of which are caused by atherosclerosis. Discerning processes that participate in macrophage-to-foam cell formation are critical for understanding the basic mechanisms underlying atherosclerosis. To explore the molecular mechanisms of foam cell formation, the differentially expressed proteins were identified. Methods: In this paper, human monocytes, macrophage colony-stimulating factor induced macrophages, and oxidized low-density lipoprotein induced foam cells were cultured, and tandem mass tag (TMT) labeling combined with mass spectrometry (MS) were performed to find associations between foam cell transformation and proteome profiles. Results: Totally, 5146 quantifiable proteins were identified, among which 1515 and 182 differentially expressed proteins (DEPs) were found in macrophage/monocyte and foam cell/macrophage, respectively, using a cutoff of 1.5-fold change. Subcellular localization analysis revealed that downregulated DEPs of macrophages/monocytes were mostly located in the nucleus and upregulated DEPs of foam cells/macrophages mostly located in the plasma membrane and extracellular. Functional analysis of DEPs demonstrated that cholesterol metabolism related proteins were upregulated in foam cells, whereas the immune response-related proteins were downregulated in foam cells. The protein-interaction network showed that the DEPs with the highest interaction intensity between macrophages and foam cells were mainly concentrated in lysosomes and the endoplasmic reticulum. Conclusions: This study for the first time to perform quantitative proteomic investigation by TMT labeling and LC-MS/MS to identify differentially expressed proteins in human monocyte, macrophage, and foam cell. The results confirmed cholesterol metabolism was upregulated in foam cells, while immune response was suppressed, which suggested that foam cells were not the population that promote inflammation. In addition, KEGG enrichment analysis and protein-protein interaction indicated that the differentially expressed proteins locating in the endoplasmic reticulum and lysosomes may be key targets to regulate foam cell formation. These data provide a basis for identifying the potential proteins associated with the molecular mechanism involved in the transformation of macrophages to foam cells.
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2021-09-09 | PXD016245 | Pride
Project description:Mutations in proteins like FUS which cause Amyotrophic Lateral Sclerosis (ALS) result in the aberrant formation of stress granules while ALS-linked mutations in other proteins impede elimination of stress granules. Repeat expansions in C9ORF72, the major cause of ALS, reduce C9ORF72 levels but how this impacts stress granules is uncertain. Here, we demonstrate that C9ORF72 associates with the autophagy receptor p62 and controls elimination of stress granules by autophagy. This requires p62 to associate via the Tudor protein SMN with proteins, including FUS, that are symmetrically arginine-methylated by PRMT5. Mice lacking p62 accumulate arginine-methylated proteins and alterations in FUS-dependent splicing. Finally, patients with C9ORF72 repeat expansions accumulate symmetric arginine dimethylated proteins which co-localize with p62. This suggests that C9ORF72 initiates a cascade of ALS-linked proteins (C9ORF72, p62, SMN, FUS) to recognize stress granules for degradation by autophagy and hallmarks of a defect in this process are observable in ALS patients.
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Project description:Macrophages play a critical role in innate immunity, and the expression of early response genes orchestrate much of the initial response of the immune system. Macrophages undergo extensive transcriptional reprogramming in response to inflammatory stimuli such as Lipopolysaccharide (LPS). To identify gene transcription regulation patterns involved in early innate immune responses, we used two genome-wide approaches - gene expression profiling and chromatin immunoprecipitation-sequencing (ChIP-seq) analysis. We examined the effect of 2 hrs LPS stimulation on early gene expression and its relation to chromatin remodeling (H3 acetylation; H3Ac) and promoter binding of Sp1 and RNA polymerase II phosphorylated at serine 5 (S5P RNAPII), which is a marker for transcriptional initiation. Our results indicate novel and alternative gene regulatory mechanisms for certain proinflammatory genes. We identified two groups of up-regulated inflammatory genes with respect to chromatin modification and promoter features. One group, including highly up-regulated genes such as tumor necrosis factor (TNF), was characterized by H3Ac, high CpG content and lack of TATA boxes. The second group, containing inflammatory mediators (interleukins and CCL chemokines), was up-regulated upon LPS stimulation despite lacking H3Ac in their annotated promoters, which were low in CpG content but did contain TATA boxes. Genome-wide analysis showed that few H3Ac peaks were unique to either +/-LPS condition. However, within these, an unpacking/expansion of already existing H3Ac peaks was observed upon LPS stimulation. In contrast, a significant proportion of S5P RNAPII peaks (approx 40%) was unique to either condition. Furthermore, data indicated a large portion of previously unannotated TSSs, particularly in LPS-stimulated macrophages, where only 28% of unique S5P RNAPII peaks overlap annotated promoters. The regulation of the inflammatory response appears to occur in a very specific manner at the chromatin level for specific genes and this study highlights the level of fine-tuning that occurs in the immune response. 2 pairs of THP-1 cells either stimulated with LPS or not. ChIP using either H3K9/K14Ac, RNA Pol II (phospho S5) or SP1 antibody. This submission represents chip-seq component of study.
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