Genome-wide DNA methylation analysis of non-cancerous urothelium obtained from patients with urothelial carcinomas and corresponding cancerous tissue
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE111933 | GEO | 2019/08/15
REPOSITORIES: GEO
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Project description:Genome-wide DNA methylation analysis of non-cancerous urothelium obtained from patients with urothelial carcinomas and corresponding cancerous tissue
| PRJNA438600 | ENA
Project description:Objectives: Much of the information to date in terms of subtypes and function of bladder urothelial cells were derived from anatomical location or by the expression of a small number of marker genes. To have a comprehensive map of the cellular anatomy of bladder urothelial cells, we performed single-cell RNA-sequencing to thoroughly characterize mouse bladder urothelium. Materials and methods: A total of 18,917 single cells from mouse bladder urothelium was analyzed by unbiased single-cell RNA sequencing. The expression of the novel cell marker was confirmed by immunofluorescence using urinary tract infections models. Results: Unsupervised clustering analysis identified 8 transcriptionally distinct cell subpopulations from mouse bladder urothelial cells. We discovered a novel type of bladder urothelial cells marked by Plxna4 that may be involved with host response and wound healing. We also found a group of basal-like cells labeled by ASPM that could be the progenitor cells of adult bladder urothelium. ASPM+ urothelial cells are significantly increased after injury by UPEC. In addition, specific transcription factors were found to be associated with urothelial cell differentiation. At the last, a number of interstitial cystitis/bladder pain syndrome-regulating genes were found differentially expressed among different urothelial cell subpopulations. Conclusions: Our study provides a comprehensive characterization of bladder urothelial cells, which is fundamental to understanding the biology of bladder urothelium and associated bladder disease.
2020-12-12 | GSE163029 | GEO
Project description:Urothelium forms a distensible yet impermeable barrier, senses and transduces stimuli, and defends the urinary tract from mechanical, chemical and bacterial injuries. Biochemical and genetic labeling studies support the existence of one or more progenitor populations with the capacity to rapidly regenerate the urothelium following injury, but slow turnover, a low mitotic index, and inconsistent methodologies obscure progenitor identity. The progenitor properties of basal Keratin 5 urothelial cells (K5-UC) have been previously investigated, but those studies focused on embryonic or adult bladder urothelium. Urothelium undergoes desquamation and apoptosis after birth, which requires postnatal proliferation and restoration. Therefore, we mapped the fate of bladder K5-UCs across postnatal development/maturation and following administration of cyclophosphamide to measure homeostatic and reparative progenitor capacities, respectively. In vivo studies demonstrate that basal K5-UCs are age-restricted progenitors in neonates and juveniles, but not in adult mice. Neonatal K5-UCs retain a superior progenitor capacity in vitro, forming larger and more differentiated urothelial organoids than adult K5-UCs. Accordingly, K5-UC transcriptomes are temporally distinct, with enrichment of transcripts associated with cell proliferation and differentiation in neonates. Induction of urothelial proliferation is sufficient to restore adult K5-UC progenitor capacity. Our findings advance the understanding of urothelial progenitors and support a linear model of urothelial formation and regeneration, which may have significant impact on therapeutic development or tissue engineering strategies.
2024-01-03 | GSE248463 | GEO
Project description:Peroxisome Proliferator-Activated Receptor-gamma (PPARG) is a nuclear hormone receptor that was originally described as a master regulator of adipogenesis but could also promote cellular differentiation in a number of epithelium. PPARG also serves as an important regulator in anti-inflammatory activity after a variety of injuries, acting in part by antagonizing the NF-kB pathway. Moreover, the expression of PPARG is strongly down regulated in the basal subtype of bladder cancer, suggesting that its removal might be essential in tumorigenesis. In urothelial cells, it has been shown that PPARG promotes urothelial differentiation in vitro, but its function in vivo remains unexplored. The urothelium is a stratified epithelium that serves as a barrier between the urinary tract and blood. It consists of terminally differentiated umbrella cells, intermediate cells which serve as umbrella cell progenitors; and unipotent basal cells. To determine the role of PPARG in vivo, we used Cre-Lox recombination to conditionally delete the Pparg gene in the mouse urothelium using the ShhCre driver, which drives recombination in basal and intermediate cells, and their respective daughters. Interestingly, ShhCre;Ppargfl/fl mutants lack umbrella and intermediate cells, but have an abnormal cell population negative for classical urothelial markers instead. Furthermore, we observed an increase of KRT14+ population in the basal compartment and squamous features in the mutant urothelium. Expression profile analysis suggested PPARG regulates metabolism, urothelial differentiation and innate immune response. We further challenged the Pparg mutant urothelium with acute injury. In wild type animals, urinary tract infection (UTI) with uropathogenic E.coli results in a transient innate immune response, followed by a completed regernation within 2 weeks. When ShhCre;Ppargfl/fl mutants were challenged with urinary tract infection, the innate immune response was not resolved even after several weeks and the Pparg ablated urothelium exhibited squamous metaplasia. RNAseq data suggested that PPARG plays a role in regulating squmous differentiation and NFkB signial pathway. Together these findings suggest that PPARG is essential for the normal differentiation of the urothelium and is a potent regulator of the inflammatory response after UTI. Understanding the link between the loss of PPARG, chronic inflammation and tumorigenesis in the urothelium could shed light on the urothelial differentiation network and pave the way for the development of therapeutic approaches to various urinary diseases.
2019-07-25 | GSE123779 | GEO
Project description:Kruppel-like transcription factor 5 (Klf5) is expressed during late embryogenesis in the forming murine bladder urothelium. Targeted disruption of the Klf5flox alleles by the ShhGfpCre transgene resulted in failure of the bladder urothelium to mature accompanied by hydronephrosis, hydroureter, and vesicoureteric reflux in all E18.5 fetuses. The bladder urothelium did not stratify nor did it express terminal differentiation markers characteristic of basal, intermediate, and umbrella cells including keratins 20, 14, and 5, and uroplakins. At E18.5, an ectopic alpha smooth muscle actin positive layer of cells was identified subjacent to the undifferentiated Klf5-deficient urothelium. The effects of Klf5 deficiency were unique to the urothelium since maturation of the epithelium comprising the bladder neck and urethra were unaffected by the lack of KLF5. mRNA microarray analysis of whole E14.5 control and Klf5 deficient bladders identified Ppar? and Grhl3 as putative downstream intermediary transcription factors that regulate urothelial maturation. Transient transfection assays demonstrated that KLF5 regulated expression of the mGrhl3 promoter. These observations show that alterations in maturation of the bladder urothelium alone are sufficient to induce bladder dysfunction leading to prenatal hydronephrosis. Total RNA from E14.5 whole bladders isolated from Klf5D/D and Klf5+/+ShhGfpCre+ embryos (n=3 samples/genotype, each sample a pool of two bladders) was isolated using the Qiagen MicroRNA Kit. The cDNA was then hybridized according to the manufacturer’s protocol to the Affymetrix Mouse Gene 1.0 ST Array
2011-08-01 | E-GEOD-27014 | biostudies-arrayexpress
Project description:To gain a more depth knowledge of repressive epigenetic gene regulation in UCC, we have profiled H3K9m3 and H3K27m3 in normal and malignant urothelial cells. We matched these profiles to those 5-methylcytosine and gene expression. We hypothesized that differences represent pro-carcinogenic events within the urothelium. We identified a panel of genes with cancer specific epigenetic mediated aberrant expression. Two repressive histone modifications (H3K9m3 and H3K27m3) , cytosine methylation and gene expression were compared between normal human urothelial cell line (NHU) and malignant urothelial cells (EJ and RT112).
2011-09-19 | E-GEOD-31864 | biostudies-arrayexpress
Project description:Analysis of differential gene expression in urothelium cancer cells compared to healthy bladder cells. The goal of researh was to discover any differences in signaling pathways regulation between cancer and normal cells and searching potential molecular markers for early cancer diagnostics. Total RNA was isolated from 9 cancerous tissue samples obtained during cystectomy and 3 normal bladder tissue samples obtaind post mortem from donors without bladder cancer.
2013-11-20 | E-GEOD-52519 | biostudies-arrayexpress
Project description:Kruppel-like transcription factor 5 (Klf5) is expressed during late embryogenesis in the forming murine bladder urothelium. Targeted disruption of the Klf5flox alleles by the ShhGfpCre transgene resulted in failure of the bladder urothelium to mature accompanied by hydronephrosis, hydroureter, and vesicoureteric reflux in all E18.5 fetuses. The bladder urothelium did not stratify nor did it express terminal differentiation markers characteristic of basal, intermediate, and umbrella cells including keratins 20, 14, and 5, and uroplakins. At E18.5, an ectopic alpha smooth muscle actin positive layer of cells was identified subjacent to the undifferentiated Klf5-deficient urothelium. The effects of Klf5 deficiency were unique to the urothelium since maturation of the epithelium comprising the bladder neck and urethra were unaffected by the lack of KLF5. mRNA microarray analysis of whole E14.5 control and Klf5 deficient bladders identified Ppar-gamma and Grhl3 as putative downstream intermediary transcription factors that regulate urothelial maturation. Transient transfection assays demonstrated that KLF5 regulated expression of the mGrhl3 promoter. These observations show that alterations in maturation of the bladder urothelium alone are sufficient to induce bladder dysfunction leading to prenatal hydronephrosis.
2011-08-02 | GSE27014 | GEO
Project description:Smoking is a major risk factor for Urothelial carcinoma (UC). However the complex mechanisms, how smoking promotes carcinogenesis and tumour progression, remain obscure. A microarray based approached was therefore performed to detect the smoking derived gene expression alteration in non-malignant and malignant urothelial tissues from patients with superficial or invasive UC. Smoking enhanced cell migration and response to tissue damages. In non-malignant tissues smoking induced immune response and altered the cytoskeleton. In urothelial carcinoma, smoking altered extracellular and chromosome structures. Smoking affected tissues from patients with invasive carcinomamore strongly, up-regulating particularly growth factors and oncogenes in non-malignant tissue of patients with invasive but not with superficial carcinoma. In former smokers, comparable changes were seen in tissues form patients with invasive disease while they were minor or reversed in tissue of patients with superficial disease. Best but not complete tissue repair was suggestedfor non-malignant tissue from patients with superficial tumours. we used microarray techniques to define gene expression profile which may explain the contribution of smoking to urothelial carcinoma. Gene expression profiling using GeneChip HG-U133A Plus 2.0 (Affymetrix) was performed on non-malignant and carcinogenic urothelium from six patients with superficial and six with invasive urothelial carcinoma, each group including two current, former, and non-smokers.
2013-03-20 | E-GEOD-21142 | biostudies-arrayexpress
Project description:Purpose: Evaluate gene expression profiles after inducing differentiation in cultured interstitial cystitis (IC) and control urothelial cells. Materials and Methods: Bladder biopsies were taken from IC patients and controls (women having surgery for stress incontinence). Primary cultures were grown in Keratinocyte Growth Medium with supplements. To induce differentiation, in some plates the medium was changed to DMEM-F12 with supplements. RNA was analyzed with Affymetrix chips. Three nonulcer IC patients were compared with three controls. Results: After inducing differentiation, 302 genes with a described function were altered at least 3-fold with p <0.01 in both IC and control cells. Functions of the162 upregulated genes included cell adhesion (e.g. claudins, occludin, cingulin); urothelial differentiation, retinoic acid pathway and keratinocyte differentiation (e.g. skin cornified envelope components). The 140 downregulated genes included genes associated with basal urothelium (e.g. p63, integrins ?4, ?5 and ?6, basonuclin 1 and extracellular matrix components), vimentin, metallothioneins and members of the Wnt and Notch pathways. Comparing IC vs. control cells after differentiation, only seven genes with a described function were altered at least 3-fold with p <0.01. PI3, SERPINB4, CYP2C8, EFEMP2 and SEPP1 were decreased in IC; AKR1C2 and MKNK1 were increased in IC. Conclusions: Differentiation-associated changes occurred in both IC and control cells. Comparing IC vs. control revealed very few differences. This study may have included IC patients with minimal urothelial deficiency and/or selected the cells that were most robust in culture. Also, the abnormal urothelium in IC may be due to post-translational changes and/or the bladder environment. Experiment Overall Design: Human female urothelial cell cultures, differentiated vs. non-differentiated,interstitial cystitis vs. control
2008-10-25 | E-GEOD-11839 | biostudies-arrayexpress