Angiopoietin-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 SamplesAn unbalanced karyotype, a condition known as aneuploidy, has a profound impact on cellular physiology and is a hallmark of cancer. Determining how aneuploidy affects cells is thus critical to understanding tumorigenesis. Here we show that aneuploidy interferes with the degradation of autophagosomes within lysosomes. Mis-folded proteins that accumulate in aneuploid cells due to aneuploidy-induced proteomic changes overwhelm the lysosome with cargo, leading to the observed lysosomal degradation defects. Importantly, aneuploid cells respond to lysosomal saturation. They activate a lysosomal stress pathway that specifically increases the expression of genes needed for autophagy-mediated protein degradation. Our results reveal lysosomal saturation as a universal feature of the aneuploid state that must be overcome during tumorigenesis. Overall design: RPE-1 cells either untreated or treated with one of Reversine, Bafilomycin A1 or MG132, each condition was done in triplicate. D14-*_Control: untreated control D14-*_Rev: cells treated with 0.5uM Reversine for 24hrs and harvested 48hrs later D14-*_Baf: cells treated with 0.1uM BafA1 for 6hrs D14-*_Mg: cells treated with 1uM MG132 for 24 hrs
Aneuploidy-induced cellular stresses limit autophagic degradation.
No sample metadata fields
View SamplesGobal expression analysis in four somatic tissues (brain, liver, kidney and muscle) of adult 40,XX and 39,XO mice with the aim of identifying which genes are expressed from both X chromosomes as well as those genes deregulated in X chromosome monosomy.
Transcriptional changes in response to X chromosome dosage in the mouse: implications for X inactivation and the molecular basis of Turner Syndrome.
Sex, Age, Specimen part
View SamplesAdipose tissue inflammation and atherosclerosis are the main mechanisms behind type 2 diabetes and cardiovascular disease respectively, the major risks associated with the metabolic syndrome. Studies considering more than single factors behind the complexity of the metabolic syndrome are valuable to achieve a better and wider understanding of the metabolic syndrome. In this study common dysregulated pathways between adipose tissue inflammation and atherosclerosis were identified using two different bioinformatic tools to perform pathway analysis. First, we run a gene set enrichment analysis utilizing with data from two microarray experiments done with gonadal white adipose tissue and atherosclerotic aorta. Once the common dysregulated pathways between both tissues were identify, the inflammatory response and the oxidative phosphorylation pathways from the Hallmark geneset were selected to conduct a deeper checkup at the single gene level of these pathways. Second, we carried out a pathway analysis validation with the Panther software combining the microarray data with a published type 2 diabetes mellitus metanalysis and cardiovascular disease metanalysis which included human data. In conclusion, this study provides worthwhile data pointing out and describing several dysregulated and common pathways in adipose tissue inflammation and atherosclerotic aorta with a potential implication in the pathogenesis of type 2 diabetes and atherosclerosis.
Common dysregulated pathways in obese adipose tissue and atherosclerosis.
Specimen part
View SamplesAneuploidy, an incorrect chromosome number, is the leading cause of miscarriages and mental retardation in humans and is a hallmark of cancer. We examined the effects of aneuploidy on primary mouse cells by generating a series of cell lines that carry an extra copy of one of four mouse chromosomes. In all four trisomic lines proliferation was impaired and metabolic properties were altered. Immortalization, the acquisition of the ability to proliferate indefinitely, was also affected by the presence of an additional chromosome, with some chromosomes inhibiting immortalization while others accelerating the process. Our data indicate that aneuploidy decreases not only organismal but also cellular fitness and elicits traits that are shared between different aneuploid cells.
Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells.
No sample metadata fields
View SamplesTo compare the gene expression profiles of unpassaged, proliferating HUVEC and human iris, retinal and choroidal microvascular endothelial cells.
Comparative gene expression profiling of human umbilical vein endothelial cells and ocular vascular endothelial cells.
Specimen part
View SamplesThe DNA methyl transferase inhibitor decitabine regulates gene expression in cancer cells.
Decitabine Enhances Lymphocyte Migration and Function and Synergizes with CTLA-4 Blockade in a Murine Ovarian Cancer Model.
Specimen part, Cell line
View SamplesCells were grown to saturation in YPD (YEP + 2% glucose) for 24 hours, diluted into YPA (YEP + 2% potassium acetate) at OD600= 0.3 and grown over night at 30C. Cells were washed with sterilized water the next day and re-suspended in SPII medium (0.3% potassium acetate, pH = 7.0) at OD600= 1.9 to induce sporulation. Cells were sporulated at room temperature or 30C as indicated. Sporulation medium containing benomyl was always prepared freshly on the day of the experiment following the directions in {Shonn, 2000 #90}. Briefly, DMSO (dimethyl sulfoxide, Sigma-Aldrich) or benomyl [Methyl 1-(butylcarbamoyl)-2-benzimidazolecarbamate, Sigma-Aldrich; 30 mg/ml stock in DMSO] was dissolved in near-boiling SPII medium to avoid precipitation. The medium was then allowed to slowly cool to 30C or room temperature. At the time of drug treatment, cells were filtered and immediately re-suspended in the medium containing benomyl or DMSO.
Novel response to microtubule perturbation in meiosis.
No sample metadata fields
View SamplesWe compare transcriptomic profiles of human induced pluripotent stem cells (iPSCs), motor neurons (MNs) in vitro differentiated from iPSCs or human ESCs containing a HB9::GFP reporter for MNs, and human fetal spinal cords.
ALS disrupts spinal motor neuron maturation and aging pathways within gene co-expression networks.
Sex
View Samples