To identify the genes and pathways regulated by FOXF2, we investigated potential FOXF2 gene targets by microarray analyses of primary prostate stromal cells (PrSC) in which FOXF2 was knocked down by siRNA. 190 differentially expressed genes were selected, of which 104 genes were more highly expressed in PrSC cells treated with FOXF2 siRNA and 86 were more highly expressed in PRSC cells treated with negative control siRNA.
The FOXF2 pathway in the human prostate stroma.
No sample metadata fields
View SamplesBackground: The prevalence of type 2 diabetes has increased dramatically in recent decades. Increasing brown adipose tissue (BAT) mass and activity has recently emerged as an interesting approach to not only increase energy expenditure, but also improve glucose homeostasis. BAT can be recruited by prolonged cold exposure in lean, healthy humans. Here, we tested whether cold acclimation could have therapeutic value for patients with type 2 diabetes by improving insulin sensitivity. Methods: Eight type 2 diabetic patients (age 59.35.8 years, BMI 29.83.2 kg/m2) followed a cold acclimation protocol, consisting of intermittent cold exposure (6 hours/day, 14-14.5 C) for 12 consecutive days. Before and after cold acclimation, cold-induced BAT activity was assessed by [18F]FDG-PET/CT scanning, insulin sensitivity at thermoneutrality by a hyperinsulinemic-euglycemic clamp, and muscle and WAT biopsies were taken. Results: Cold-induced BAT activity was low, but increased in all patients upon cold acclimation (SUV from 0.400.29 to 0.630.78, p<0.05). Interestingly, insulin sensitivity showed a very pronounced 40% increase upon cold acclimation (glucose rate of disappearance from 14.94.1 to 20.56.9 mol kg-1 min-1, p<0.05). A 40% increase in insulin sensitivity cannot be explained by BAT glucose uptake, in fact basal skeletal muscle GLUT4 content and translocation was markedly increased after cold acclimation, without effects on insulin signaling or AMPk activation. Conclusions: Regular mild cold exposure has marked effects on insulin sensitivity, which are accompanied by small increases in BAT activity and more pronounced effects on skeletal muscle. These data suggest a novel therapeutic option for the treatment of type 2 diabetes.
Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus.
Subject
View SamplesCytotoxic T cells confer a prognostic benefit in many tumors, including ovarian cancer. We and others have previously identified a subset of CD8+ T cells, namely CD103+CD8+ T cells, that seems to have a better prognostic effect. The aim of this study is to identify how these CD103+ T cells differ from CD103-CD8+ T cells on mRNA level in human samples of ovarian cancer. Overall design: mRNA profiles of 10 pools of 20 cells CD103+CD8+, 10 pools of 20 cells CD103-CD8+, 20 single-cells CD103+CD8+, 20 single-cells CD103-CD8+ were generated from TILs of 3 ovarian cancers (high-grade serous ovarian cancer) by SMARTseq2
A Transcriptionally Distinct CXCL13<sup>+</sup>CD103<sup>+</sup>CD8<sup>+</sup> T-cell Population Is Associated with B-cell Recruitment and Neoantigen Load in Human Cancer.
Subject
View SamplesHuman lymphoid tissues harbor, in addition to CD56bright and CD56dim natural killer (NK) cells, a third NK cell population: CD69+CXCR6+ lymphoid tissue (lt)NK cells. The function and development of ltNK cells remain poorly understood. In this study we performed RNA sequencing on the CD56bright and CD56dim NK cells (from bone marrow and blood), and the ltNK cells (from bone marrow). In addition, the blood derived CD56dim, and bone marrow derived ltNK cells were further subdivided into a NKG2A+ and NKG2A- fraction. Paired blood and bone marrow samples of 4 healthy donors were included. When comparing the NKG2A fractions, only 3 genes (of 9382 genes included) had a significantly differential expression. Therefore, we pooled the expression data proportionally from the NKG2A+ and NKG2A- fractions in subsequent analyses. In ltNK cells, 1353 genes were differentially expressed compared to circulating NK cells. Several molecules involved in migration were downregulated in ltNK cells: S1PR1, SELPLG and CD62L. By flow cytometry we confirmed that the expression profile of adhesion molecules (CD49e-, CD29low, CD81high, CD62L-, CD11c-) and transcription factors (Eomeshigh, Tbetlow) of ltNK cells differed from their circulating counterparts. LtNK cells were characterized by enhanced expression of inhibitory receptors TIGIT and CD96 and low expression of DNAM1 and cytolytic molecules (GZMB, GZMH, GNLY). Their proliferative capacity was reduced compared to the circulating NK cells. By performing gene set enrichment analysis we identified DUSP6 and EGR2 as potential regulators of the ltNK cell transcriptome. Remarkably, comparison of the ltNK cell transcriptome to the published human spleen-resident memory CD8+ T (Trm) cell transcriptome revealed an overlapping gene signature. Moreover, the phenotypic profile of ltNK cells resembled that of CD8+ Trm cells in bone marrow. Together, we provide a comprehensive molecular framework of the conventional CD56bright and CD56dim NK cells as well as the tissue-resident ltNK cells and provide a core gene signature which might be involved in promoting tissue-residency. Overall design: mRNA sequencing of NK cell populations isolated from blood: CD56bright, NKG2A+ CD56dim and NKG2A- CD56dim, and bone marrow: CD56bright, CD56dim, NKG2A+ ltNK, and NKG2A- ltNK. Each sample has 4 biological replicates.
Human Bone Marrow-Resident Natural Killer Cells Have a Unique Transcriptional Profile and Resemble Resident Memory CD8<sup>+</sup> T Cells.
Specimen part, Subject
View SamplesTo gain more insight into initiation and regulation of T cell receptor (TCR) gene rearrangement during human T cell development, we analyzed TCR gene rearrangements by quantitative PCR analysis in nine consecutive T-cell developmental stages, including CD34+ lin- cord blood cells as a reference. The same stages were used for gene expression profiling using DNA microarrays.
New insights on human T cell development by quantitative T cell receptor gene rearrangement studies and gene expression profiling.
Specimen part
View SamplesT cells develop from progenitors that migrate from the bone marrow into the thymus. Thymocytes are subdivided roughly as being double negative (DN), double positive (DP), or single positive (SP), based on the expression of the CD4 and CD8 coreceptors. The DN stage is heterogeneous and can be subdivided into four distinct subsets in mice based on the expression of CD44 and CD25. In human, three distinct DN stages can be recognized: a CD34+CD38CD1a stage that represents the most immature thymic subset and the consecutive CD34+CD38+CD1a and CD34+CD38+CD1a+ stages. Human DN thymocytes mature via an immature single positive (ISP CD4+) and a DP stage into CD4+ or CD8+ SP T cells that express functional T cell receptors (TCR) and that exit the thymus. In this study, gene expression was measured in each of these nine stages.
New insights on human T cell development by quantitative T cell receptor gene rearrangement studies and gene expression profiling.
No sample metadata fields
View SamplesGene expression information is useful in prioritizing candidate genes in linkage intervals. The data can also identify pathways involved in the pathophysiology of disease.
Integration of expression profiles and genetic mapping data to identify candidate genes in intracranial aneurysm.
Sex, Age, Specimen part, Race
View SamplesAngiopoietin-like protein 4 (ANGPTL4, also referred to as Fiaf) has been proposed as circulating mediator between the gut microbiota and fat storage in adipose tissue. Very little is known about mechanisms of regulation of ANGPTL4 in the colon. Here we show that transcription and subsequent secretion of ANGPTL4 in human T84 and HT-29 colonocytes is highly induced by physiological concentrations of products of bacterial fermentation, the short chain fatty acids (SCFA). Induction of ANGPTL4 by SCFA cannot be mimicked by the histone deacetylase inhibitor Trichostatin A. SCFA induce ANGPTL4 by activating the nuclear receptor PPAR, as shown by use of PPAR antagonist, PPAR knock-down, and transactivation assay, which shows activation of PPAR but not PPAR and PPAR. At concentrations required for PPAR activation and ANGPTL4 induction in colonocytes, SCFA do not stimulate PPAR in mouse 3T3-L1 and human SGBS adipocytes, suggesting that SCFA act as selective PPAR modulators (SPPARM), which is supported by coactivator peptide recruitment assay and structural modelling. Consistent with the notion that fermentation leads to PPAR activation in vivo, feeding mice a diet rich in inulin was associated with induction of PPAR target genes and pathways in the colon, as shown by microarray and subsequent gene set enrichment analysis. It can be concluded that 1) SCFA potently stimulate ANGPTL4 synthesis in human colonocytes; 2) SCFA transactivate and bind to PPAR by serving as selective PPAR modulators. Our data point to activation of PPAR as a novel mechanism of gene regulation by SCFA in the colon.
Short-chain fatty acids stimulate angiopoietin-like 4 synthesis in human colon adenocarcinoma cells by activating peroxisome proliferator-activated receptor γ.
Sex, Age, Specimen part
View SamplesAngiopoietin-like protein 4 (ANGPTL4, also referred to as Fiaf) has been proposed as a circulating mediator between the gut microbiota and fat storage in adipose tissue. Very little is known about the mechanisms of regulation of ANGPTL4 in the colon. Here we show that transcription and subsequent secretion of ANGPTL4 in human T84 and HT-29 colonocytes is highly induced by physiological concentrations of products of bacterial fermentation, the short-chain fatty acids. Short-chain fatty acids induce ANGPTL4 by activating the nuclear receptor PPAR, as shown by microarray, transactivation assays, coactivator peptide recruitment assay, and use of PPAR antagonist. At concentrations required for PPAR activation and ANGPTL4 induction in colonocytes, SCFA do not stimulate PPAR in mouse 3T3-L1 and human SGBS adipocytes, suggesting that SCFA act as selective PPAR modulators (SPPARM), which is supported by coactivator peptide recruitment assay and structural modelling. It can be concluded that 1) SCFA potently stimulate ANGPTL4 synthesis in human colonocytes, and 2) SCFA transactivate and bind to PPAR by serving as selective PPAR modulators. Our data point to activation of PPAR as a novel mechanism of gene regulation by SCFA in the colon.
Short-chain fatty acids stimulate angiopoietin-like 4 synthesis in human colon adenocarcinoma cells by activating peroxisome proliferator-activated receptor γ.
Specimen part, Cell line, Treatment
View SamplesThis SuperSeries is composed of the SubSeries listed below.
HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration.
Sex, Age, Specimen part
View Samples