Athsq1 is linked to Cdkn2a
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE24342 | GEO | 2011/10/01
SECONDARY ACCESSION(S): PRJNA132903
REPOSITORIES: GEO
Similar Datasets
Project description:Common genetic variants in a 58-kilobase (kb) region of chromosome 9p21, near the CDKN2A/B cell proliferation inhibitor genes, are strongly associated with coronary artery disease (CAD). We previously reported a congenic mouse model harboring an atherosclerosis susceptibility locus in a region of homology with the human 9p21 locus. We now report markedly decreased Cdkn2a (cyclin-dependent kinase inhibitor 2a) mRNA expression in macrophages and increased circulating levels of Ly6Chigh inflammatory monocytes in congenic mice compared to controls. A bone marrow (BM) transplantation study revealed that BM-derived cells from Cdkn2a+/- mice are capable of conferring accelerated atherosclerosis, increased inflammatory monocyte subsets and monocyte proliferation in the Ldlr-/- mouse model. These findings provide a mechanistic link between decreased expression of Cdkn2a transcripts, increased monocyte proliferation, and accelerated atherosclerosis. Aorta and macrophages from ten C57BL/6.MOLFc4(51Mb)-Ldlr-/- mice and their control C57BL/6-Ldlr-/- were obtained, RNA purified and hybridized to GPL9734 Affimetrix microarrays.
2011-09-30 | E-GEOD-24342 | biostudies-arrayexpress
Project description:The chromosome 9p21 locus comprises several tumor suppressor genes including MTAP, CDKN2A and CDKN2B, and its homo- or heterozygous deletions are associated with reduced survival in multiple cancer types. We report that mice with germline monoallelic deletion or induced biallelic deletion of the 9p21-syntenic locus (9p21s) developed fatal myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN)-like disease associated with aberrant trabecular bone formation and/or fibrosis in the bone marrow (BM). Reciprocal BM transfers and conditional targeting of 9p21s suggested that the disease originates in the BM stroma. Single-cell analysis of 9p21s-deficient BM stroma revealed the expansion of chondrocyte and osteogenic precursors, reflected in increased osteogenic differentiation in vitro. It also showed reduced expression of factors maintaining hematopoietic stem/progenitor cells, including Cxcl12. Accordingly, 9p21s-deficient mice showed reduced levels of circulating Cxcl12 and a concomitant upregulation of the pro-fibrotic chemokine Cxcl13. Our study highlights the potential of mutations in the BM microenvironment to drive MDS/MPN-like disease. We then performed gene expression profiling analysis using data obtained from RNA-seq of 4 different cells at two time points.
2023-06-06 | GSE211779 | GEO
Project description:While melanomas commonly harbor losses of 9p21, on which CDKN2A resides, the presence of additional tumor suppressor elements at this locus is incompletely characterized. Here we assess the expression levels and functional role of microRNA-876 (miR-876), whose gene also maps to 9p21.
2024-08-21 | GSE267789 | GEO
Project description:Frequent deletion of the CDKN2A locus in chordoma: analysis of chromosomal imbalances using array comparative genomic hybridization DNA copy number analysis of 21 fresh frozen chordoma biopsies, and the respective relapse in four of them, using 32k and 1Mb array CGH. All cases showed copy number alterations and primarily deletions of chromosomal regions were found. Particularly, the CDKN2A and CDKN2B loci in 9p21 were homo- or heterozygously lost in 70% of the tumors. Keywords: chordoma, array comparative genomic hybridization
2008-01-25 | GSE9023 | GEO
Project description:Circulating TRAIL is reduced in cardiovascular disease patients and TRAIL deletion in mice exacerbates disease. The source of TRAIL and protective mechanism(s) are unclear. Monocyte TRAIL mRNA was reduced from coronary artery disease patients, strikingly associating with reduced plasma TRAIL. A strong inverse correlation between plasma TRAIL and IL-18 was observed, with IL-18 repressing monocyte TRAIL mRNA. In mice, two sources were investigated using bone-marrow (BM) transplants; TRAIL expressed only in BM (BM-TRAIL) or everywhere except BM (parenchymal-TRAIL), vs. whole-body TRAIL ablation (null-TRAIL). BM-TRAIL attenuated macrophage content and atherosclerosis. BM-derived macrophages with TRAIL deletion were more inflammatory, with impaired migration and reduced expression of cholesterol efflux, efferocytosis and nitric oxide-controlling genes. TRAIL expression also reduced islet macrophage content, but only parenchymal-TRAIL islets had improved function. Recombinant TRAIL administration stimulated insulin expression and islet mass. We propose TRAIL maintains monocyte/macrophage homeostasis and limits the progression of atherosclerosis and islet dysfunction.
2019-12-03 | GSE107645 | GEO
Project description:Frequent deletion of the CDKN2A locus in chordoma: analysis of chromosomal imbalances using array comparative genomic hybridization DNA copy number analysis of 21 fresh frozen chordoma biopsies, and the respective relapse in four of them, using 32k and 1Mb array CGH. All cases showed copy number alterations and primarily deletions of chromosomal regions were found. Particularly, the CDKN2A and CDKN2B loci in 9p21 were homo- or heterozygously lost in 70% of the tumors. Cases 1-11 were analyzed using 32k array CGH and male genomic DNA (Promega) was used as reference. Cases 17-26, and the respective relapse in four of these tumors, were analyzed with 1 Mb array CGH, using sex matched controls.
2008-01-24 | E-GEOD-9023 | biostudies-arrayexpress
Project description:Rheumatoid arthritis (RA) accompanies infiltration and activation of monocytes in inflamed joints. In this study we investigated dominant alterations of RA monocytes in bone marrow (BM), blood and inflamed joints. CD14+ cells from BM and blood of RA and osteoarthritis (OA) patients were profiled with Affymetrix HG U133 Plus 2.0 Arrays. Detailed functional analysis was performed with reference transcriptomes of BM precursors, monocyte blood subsets, monocyte activation and mobilization. Cytometric profiling determined monocyte subsets of CD14++CD16-, CD14++CD16+ and CD14+CD16+ cells in BM, blood and synovial fluid (SF) and ELISAs quantified the release of activation markers into SF and serum. Investigation of genes differentially expressed between RA and OA monocytes by co-expression analysis with reference transcriptomes revealed gene patterns of early myeloid precursors in RA-BM and late myeloid precursors along with reduced terminal differentiation to CD14+CD16+ monocytes in RA blood. Patterns associated with TNF/LPS stimulation were weak and more pronounced in RA blood than BM. Cytometric phenotyping of cells in BM and blood disclosed differences related to monocyte subsets and confirmed the reduced frequency of terminally differentiated CD14+CD16+ monocytes in RA blood, as suggested by transcriptome data. Monocyte activation in SF was characterized by the predominance of CD14++CD16++CD163+HLA-DR+ cells and elevated concentrations of sCD14, sCD163 and S100P. Accelerated monocytopoiesis, BM egress and migration into inflamed joints characterise increased monocyte turnover in RA. Predominant activation in the joint suggests local and primary stimulants, which may promote also adaptive immune triggering through monocytes, thus indicating their importance for diagnostic and therapeutic strategies.
2017-07-05 | GSE100786 | GEO
Project description:Supranormal levels of aldosterone are associated with increased cardiovascular risk in humans, and with accelerated atherosclerosis in animal models. Atherosclerosis is a low-grade inflammatory disorder, with monocyte-derived macrophages as major drivers of plaque formation. Monocytes can adopt a long-term pro-inflammatory phenotype after brief stimulation with microbial pathogens or endogenous atherogenic lipoproteins via a process termed trained immunity. Using a primary human in vitro model, we demonstrate that aldosterone induces trained immunity via the mineralocorticoid receptor. We identify fatty acid synthesis as a crucial pathway necessary for the induction of trained immunity in monocyte-derived macrophages and demonstrate that pharmacological inhibition of this pathway blunts aldosterone-induced trained immunity. At the level of gene regulation, aldosterone promotes enrichment of the transcriptionally-permissive H3K4me3 modification at promoters of genes central to the fatty acid synthesis pathway. These data provide mechanistic insight into the contribution of aldosterone to inflammation, atherosclerosis and cardiovascular disease.
2020-09-21 | GSE121696 | GEO
Project description:Accumulation of senescent cells with age is believed to be an important driver of aging and age-related diseases. However, the underlying mechanisms and the signaling pathways that regulate senescence remain elusive. In this report, we couple high throughput (HTP) mapping of disease-associated functional SNPs (fSNPs) with proteomics analysis of fSNP-binding regulatory proteins to dissect the CDKN2A/B locus, a locus known to be associated with multiple age-related diseases, as well as overall human longevity. We demonstrate that the homeodomain transcription factor CUX1 specifically binds to a fSNP (rs1537371) associated with atherosclerosis within the CDKN2A/B locus. Although it binds at a considerable distance (> 100 kb), CUX1 is shown to regulate the CDKN2A/B encoded genes p14ARF, p15INK4b, p16INK4a, and ANRIL in endothelial cells (ECs). In-depth analysis demonstrates that endothelial CUX1 expression correlates with telomeric length and is induced by both DNA-damaging agents and oxidative stress. Moreover, induction of CUX1 expression triggers both replicative and stress-induced premature senescence via activating p16INK4A expression. Consistent with these findings, we also detect elevated expression of CUX1 and p16INK4A in the plaques of patients with carotid artery disease. Our HTP strategy therefore identifies CUX1 as a regulator of p16INK4A expression and endothelial senescence and a potential therapeutic target for atherosclerosis and other age-related diseases.
2021-12-05 | GSE186528 | GEO
Project description:In order to simulate the effects of shear stress in regions of the vasculature prone to developing atherosclerosis, we subjected human umbilical vein endothelial cells to reversing shear stress, in order to mimic hemodynamic conditions at the wall of the carotid sinus, a site of complex, reversing blood flow and commonly observed atherosclerosis. We compared the effects of reversing shear stress (time-average 1 dyne/cm2, maximum +11 dynes/cm2, minimum -11 dynes/cm2, 1 Hz), arterial steady shear stress (15 dynes/cm2), and low steady shear stress (1 dyne/cm2) in terms of gene expression, cell proliferation, and monocyte adhesiveness. Microarray analysis revealed most differentially expressed genes were similarly regulated by all three shear stress regimens when compared to static culture. Comparisons of the three shear stress regimens to each other allowed identification of 138 genes regulated by low average shear stress and 22 by fluid reversal. Functional assays indicated that low average shear stress induces increased cell proliferation as compared to high shear stress. Reversing shear stress was the only condition that induced monocyte adhesion. Monocyte adhesion was partially inhibited by incubation of the endothelial cells with ICAM-1 blocking antibody. Increased surface heparin sulfate proteoglycan expression was observed in cells exposed to reversing shear stress. When these cells were treated with heparinase III monocyte adhesion was significantly reduced. Our results suggest that low steady shear stress is the major impetus for differential gene expression and cell proliferation, while reversing flow regulates monocyte adhesion.
2009-11-16 | GSE16706 | GEO