Role of loss of Pofut1 expression on self-renewal and differentiation of adult neural progenitor cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE97610 | GEO | 2018/04/16
REPOSITORIES: GEO
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Project description:The UT-A1 urea transporter is crucial to the kidney’s ability to generate concentrated urine. Native UT-A1 from kidney inner medulla (IM) is a heavily glycosylated protein with two glycosylation forms of 97 and 117 kDa. In diabetes, UT-A1 protein abundance, particularly the 117 kD isoform, is significantly increased corresponding to an increased urea permeability in perfused IM collecting ducts, which plays an important role in preventing the osmotic diuresis caused by glucosuria. In this study, using sugar-specific binding lectins, we found that the carbohydrate structure of UT-A1 is also changed under diabetic conditions with increased amounts of sialic acid, fucose, and increased glycan branching. These changes were accompanied by altered UT-A1 association with the galectin proteins, α-galactoside glycan binding proteins. To explore the molecular basis of the alterations of glycan structures, the highly sensitive next generation sequencing (NGS) technology, Illumina RNA-seq, was employed to analyze genes involved in the process of UT-A1 glycosylation using streptozotocin (STZ) - induced diabetic rat kidney as the tissue source. Differential expression analysis combining quantitative PCR revealed that a number of important glycosylation related genes were changed under diabetic conditions. These genes include the glycosyltransferase genes Mgat4a, the sialylation enzymes St3gal1 and St3gal4and glycan binding protein galectin-3, -5, -8 and -9. In contrast, although highly expressed in kidney IM, the glycosyltransferase genes Mgat1, Mgat2, and fucosyltransferase Fut8, did not show any changes. We conclude that the alteration of these glycosylation related genes may contribute to changing the UT-A1 glycan structure, and therefore modulate kidney urea transport activity under diabetic conditions.
2017-02-09 | GSE69548 | GEO
Project description:MTD project_description Inflammation and decreased stem cell function characterize organism aging, yet the relationship between these factors remains incompletely understood. This study shows that aged hematopoietic stem and progenitor cells exhibit increased ground-stage NF-κB activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-κB signals, by increasing chromatin accessibility of inter-/intra-genic and enhancer regions. Rad21/NF-κB are required for normal differentiation, but limit self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-κB dependent manner. HSCs from aged mice fail to downregulate Rad21/cohesin and inflammation/differentiation inducing signals in the resolution phase after acute inflammation. and The inhibition of cohesin/NF-κB is sufficient to revert the hypersensitivity of aged HSPCs to inflammation-induced differentiation. During aging, myeloid-biased HSCs with disrupted and naturally occurring reduced expression of Rad21/cohesin are increasingly selected over lymphoid-biased HSCs. Together, Rad21/cohesin mediated NF-κB signaling limits HSPC function during aging and selects for cohesin deficient HSCs with myeloid skewed differentiation.
2018-11-28 | PXD011537 | Pride
Project description:Dr. Stanley's laboratory is interested in 1) understanding the biological roles of specific classes of N-glycan in development and immunity through studies of glycosyltransferase mutant mice, 2) identifying complex binding specificities of galectins using a panel of CHO glycosylation mutants, and 3) determining how O-fucose glycans function in Notch receptor signaling and in modulating the interaction of Notch receptors with their ligands. The bisecting GlcNAc on N-glycans inhibits ricin binding and enhances E-PHA binding. It is expected that mammalian CBP's, including galectins, may have their binding affected positively or negatively by the presence of the bisecting GlcNAc. In fact unpublished experiments have identified reduced binding of at least one galectin to LEC10 CHO cells that express GlcNAc-TIII compared to CHO cells that do not. We have shown that the Mgat3 gene that encodes GlcNAc-TIII, the glycosyltransferase that adds the bisecting GlcNAc, is barely expressed in E9.5 mouse embryos and robustly expressed in E10.5 embryos (J. Biol. Chem. 277, 26300-26309; 2002). We wish to compare glycosylation and lectin genes that are expressed at E10.5 in the brain of embryos from wild type and Mgat3 knockout embryos. RNA samples were prepared from several embryo heads (3) from Mgat3+/+ and Mgat3-/- E10.5 embryos. We hybridized the RNA to glyco-chips (in triplicate per sample for a total of 6) so we can detect changes in the expression of glyco-genes as well as signaling pathway genes that may be affected.
2011-02-04 | E-GEOD-27055 | biostudies-arrayexpress
Project description:Glycosylation is the most common post-translational modification of proteins, yet genes relevant to the synthesis of glycan structure and function are incompletely represented and poorly annotated on the commercially available arrays. To fill the need for expression analysis of such genes we employed the Affymetrix technology to develop a focused and highly annotated glycogene chip representing human and murine glycogenes, including glycosyltranferases, nucleotide sugar transporters, glycosidases, proteoglycans and glycan-binding proteins. In this report the array has been used to generate glycogene expression profiles of nine murine tissues. Global analysis with a hierarchical clustering algorithm, reveals that expression profiles in immune tissues (thymus, spleen, lymph node and bone marrow) are more closely related, relative to those of non-immune tissues (kidney, liver, brain and testes). Of the biosynthetic enzymes, those responsible for synthesis of the core regions of N-and O-linked oligosaccharides are ubiquitously expressed, while glycosyltransferase that elaborate terminal structures are expressed in a highly tissue-specific manner, accounting for tissue and ultimately cell type-specific glycosylation. Comparison of gene expression profiles with MALDI-TOF profiling of N-linked oligosaccharides suggested that the alpha-1-3 fucosyltransferase IX, Fut9, is the enzyme responsible for terminal fucosylation in kidney and brain, a finding validated by analysis of Fut9 knockout mice. Two families of glycan-binding proteins, C-type lectins and siglecs, are predominately expressed in the immune tissues, consistent with their emerging functions in both innate and acquired immunity. The glycogene chip reported in this study is available to the scientific community through the Consortium for Functional Glycomics (http://www.functionalglycomics.org). Keywords: Glycogenes, Glycomics, Glycosyltransferase, Lectin, Glycosylation, Glycome, Microarray, Kidney, Fut9
2005-06-20 | GSE2781 | GEO
Project description:High-resolution proteomic analysis of acute myeloid leukemia (AML) stem cells identified phospholipase C- and Ca++-signaling pathways to be differentially regulated in AML1-ETO (AE) driven leukemia. Phospholipase C gamma 1 (Plcg1) could be identified as a direct target of the AE fusion. Genetic Plcg1 inactivation abrogated disease initiation by AE, reduced intracellular Ca++-release and inhibited AE-driven self-renewal programs. In AE-induced leukemia, Plcg1 deletion significantly reduced disease penetrance, number of leukemia stem cells and abrogated leukemia development in secondary recipient hosts. In human AE-positive leukemic cells inactivation of Plcg1 reduced colony formation and AML development in vivo. In contrast, Plcg1 was dispensable for maintenance of murine and human hematopoietic stem- and progenitor cells (HSPCs). Pharmacologic inhibition of Ca++-signaling downstream of Plcg1 resulted in impaired proliferation and self-renewal capacity in AE-driven AML. Thus, the Plcg1 pathway represents a novel specific vulnerability of AE-driven leukemia and poses an important new therapeutic target.
2022-01-12 | PXD011251 | Pride
Project description:Purpose: Aberrant glycosylation has been known to regulate cancer cell trafficking via promoting intravascular adhesion during metastasis. Clinicopathological studies have also shown a strong correlation between aberrant glycosylation and invasive/metastatic potentials of human cancers. However, the major glycosylation enzymes that drive lung cancer metastases and the signaling networks involved in the process remain incompletely understood. Methods: Two lung adenocarcinoma cell lines, A549 and CL1-0 cells, with FUT4 overexpression and 81 lung cancer tissues and 19 adjacent lung tissues underwent RNA extraction for RNA-seq analysis. Results: We identified fucosyltransferase 4 (FUT4) as a strong predictor of patient prognosis from this RNA-seq cohort. Conclusions: High levels of FUT4 in tumor tissues significantly correlate with poor prognosis in NSCLC patients.
2020-07-15 | GSE120622 | GEO
Project description:Dr. Stanley's laboratory is interested in 1) understanding the biological roles of specific classes of N-glycan in development and immunity through studies of glycosyltransferase mutant mice, 2) identifying complex binding specificities of galectins using a panel of CHO glycosylation mutants, and 3) determining how O-fucose glycans function in Notch receptor signaling and in modulating the interaction of Notch receptors with their ligands.
2011-02-04 | GSE27055 | GEO
Project description:With their ability to self-renew and simultaneously fuel the bulk tumor mass with highly proliferative tumor cells, cancer stem cells (CSC) are supposedly driving cancer progression. However, the CSC-phenotype in colorectal cancer (CRC) is unstable and dependent on environmental cues. Since FGF2 is essential for adult and embryonic stem cell culture to maintain self-renewal, we investigated its role in advanced CRC using tumor-derived organoids as experimental model. We found that FGF-Receptor (FGFR) inhibition prevents organoid formation in very early expanding cells but induces cyst formation when applied to already established organoids. Comprehensive transcriptome analyses revealed that the induction of the transcription factor activator protein-1 (AP-1) together with a MAPK stimulation was most prominent after FGFR-inhibition. These effects resemble mechanisms of an acquired resistance against other described tyrosine kinase inhibitors such as targeted therapies against the EGF-Receptor. Furthermore, we detected elevated expression levels of several self-renewal and stemness-associated genes in organoid cultures with active FGF2 signaling. The combined data assumes that CSC are a heterogeneous subpopulation while self-renewal is a common feature regulated by many different pathways. Finally, we highlight the effects of FGF2 signaling as one of numerous aspects of the complex regulation of stemness in cancer.
2020-09-01 | GSE118949 | GEO
Project description:In the past few years, mammary cancer initiating cells (CICs) have been identified in mouse and human as a subpopulation of tumor cells that selectively posses tumor initiation and self-renewal capacity and the ability to give rise to bulk populations of non-tumorigenic cancer cells progeny through differentiation. They could also be responsible for tumor progression, metastasis, resistance to therapy and recurrence. Thus, the understanding of the pathways regulating CIC self-renewal, differentiation and tumorigenicity represents an important task in the development of effective anticancer therapies. To detect the set of genes associated to CIC in our mouse breast cancer model we analysed three prototypic situations: TUBO cells grown in DMEM under adherent conditions (called TDA in GSE26517 and epithelial bulk in GSE21451), TUBO cells grown in mammosphere medium under adherent conditions (called TMA in GSE26517), TUBO cells grown in mammosphere medium under low-attachment conditions (called mammospheres p1 in GSE21451), i.e. the conditions used to support the formation of mammospheres. This analysis led to the identification of growth factors and immune system-related genes, including toll-like receptor 2 (TLR2). The inhibition of TLR2 signaling pathway strongly impaired mammosphere generation, demonstrating the involvement of TLR2 in CSC self-renewal. We profiled on MouseWG?6 v2.0 Illumina beadchips two independent experiments: ADHERENT (GSE26517) made by the comparison between TDA and TMA and SOSPENSION (part of GSE21451) made by the comparison between epithelial bulk and mammospheres p1. Mammosphere medium contains epidermal growth factor (EGF), insulin and basic fibroblast growth factor (bFGF) that may influence transcript expression in a way not necessarily related to the assembly of mammospheres. Therefore, following normalization and removal of those transcripts not expressed and not changing, we used the Integrative Correlation coefficient (IC, Parmigiani et al. Clin Cancer Res 2004, 10:2922–2927) as filter to remove genes only associate to growth factors present in the mammosphere medium under adherent growth conditions, i.e IC > 0.1. Differential gene expression was then assessed by regularized t?test (Smyth GK. Stat Appl Genet Mol Biol 2004, 3:Article3) comparing mammospheres p1 with respect to epithelial bulk, using an uncorrected p-value ? 0.05, together with an absolute log2 fold change threshold ?1.
2013-11-30 | E-GEOD-26527 | biostudies-arrayexpress
Project description:Aberrant glycosylation involves multifaceted pathological and pathophysiological changes in pancreatic ductal adenocarcinoma (PDAC), including but not limited to conferring tumor cells the ability to resist cell death. Ferroptosis driven by lethal lipid peroxidation provides a targetable vulnerability to PDAC. However, the crosstalk between glycosylation and ferroptosis remains unclear. Here, we identified 4F2hc, a subunit of the glutamate-cystine antiporter system Xc–, its N-glycosylation is involved in PDAC ferroptosis by N- and O-linked glycoproteomics. Knockdown of SLC3A2 (gene name of 4F2hc) or blocking the N-glycosylation of 4F2hc potentiates ferroptosis sensitization of PDAC cells by impairing the activity of system Xc– manifested by a marked decrease in intracellular glutathione. To identify which glycosyltransferases are critical for glycosylation initiation during ferroptosis execution. We collected 207 glycosyltransferase genes (GTGs) and performed parallel RNA-seq to reveal that the glycosyltransferase B3GNT3 catalyzes the glycosylation of 4F2hc, which stabilizes the 4F2hc protein as well as its interaction with xCT. Additionally, upon the combination with a ferroptosis inducer, treatment with the classical N-glycosylation inhibitor tunicamycin (TM) markedly triggered the overactivation of lipid peroxidation and enhanced the sensitivity of PDAC cells to ferroptosis. Notably, we confirmed that genetic perturbation of SLC3A2 or combination treatment with TM markedly increased ferroptosis sensitivity in the orthotopic PDAC model. Clinically, high expression of 4F2hc and B3GNT3 contributes to the progression and poor survival of PDAC patients. Collectively, our findings reveal a previously unappreciated function of N-glycosylation of 4F2hc in ferroptosis and suggest that targeting glycosylated 4F2hc can induce susceptibility to ferroptosis in PDAC.
2023-07-12 | GSE207741 | GEO