Genome-wide map of GATA6 DNA binding in human PDAC cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE47535 | GEO | 2015/02/03
SECONDARY ACCESSION(S): PRJNA205985
REPOSITORIES: GEO
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Project description:By studying a mouse model, as well as human tumors samples and cell lines, we have revealed a tumor suppressive role for Gata6 in the pathogenesis of pancreatic ductal adenocarcinoma (PDAC). In order to understand the mechanism underlying such tumor suppressive function, we analyzed the genome-wide DNA-binding of GATA6 in a human PDAC cell line (PaTu8988S). GATA6 is found to bind the promoter of genes involved in the epithelial differentiation programme, as well as of genes involved in the mesenchymal programme. With this we describe a novel GATA6-dependent mechanism of regulation of EMT. Examination of GATA6 binding to the DNA in a human PDAC cell line
2015-02-03 | E-GEOD-47535 | biostudies-arrayexpress
Project description:We describe the genome-wide DNA-binding of GATA6 in a human CRC cell line (LS174T). GATA6 is found to bind the promoter of genes involved in the maintenance of intestinal stem cells, including genes of the Wnt and TGFbeta/BMP pathways. With this we describe a novel GATA6-dependent mechanism of stem cell maintenance in colorectal tumors. Examination of GATA6 binding and H3K4me1, H3K4me3 and H3K27ac levels in a human CRC cell line by Chromatin immunoprecipitation followed by deep sequencing.
2014-05-20 | E-GEOD-49320 | biostudies-arrayexpress
Project description:We describe the genome-wide DNA-binding of GATA6 in a human CRC cell line (LS174T). GATA6 is found to bind the promoter of genes involved in the maintenance of intestinal stem cells, including genes of the Wnt and TGFbeta/BMP pathways. With this we describe a novel GATA6-dependent mechanism of stem cell maintenance in colorectal tumors.
2014-05-20 | GSE49320 | GEO
Project description:We have previously described in mouse models that pancreas-specific deletion of Gata6 results in pancreas alterations by rendering pancreatic acinar cells in a non-fully differentiation state, and furthermore it accelerates tumor initiation and progression in a pro-tumorigenic context (KrasG12V expression). We aim to determine the sites where Gata6 binds at the genome-wide level in the pancreas to unveil why its loss leads to altered pancreatic function and enhanced tumor formation when coexpressed with KrasG12V. Gata6 ChIP-Seq in the mouse pancreas
2015-02-03 | E-GEOD-57090 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by late diagnosis and treatment resistance. Recurrent genetic alterations in defined genes in association with perturbations of developmental cell signaling pathways have been associated with PDAC development and progression. Here, we show that GATA6 contributes to pancreatic carcinogenesis during the temporal progression of pancreatic intraepithelial neoplasia by virtue of Wnt pathway activation. GATA6 is recurrently amplified by both quantitative-PCR and fluorescent in-situ hybridization in human pancreatic intraepithelial neoplasia and in PDAC tissues, and GATA6 copy number is significantly correlated with overall patient survival. Forced overexpression of GATA6 in cancer cell lines enhanced cell proliferation and colony formation in soft agar in vitro and growth in vivo, as well as increased Wnt signaling. By contrast siRNA mediated knockdown of GATA6 led to corresponding decreases in these same parameters. The effects of GATA6 were found to be due to its ability to bind DNA, as forced overexpression of a DNA-binding mutant of GATA6 had no effects on cell growth in vitro or in vivo, nor did they affect Wnt signaling levels in these same cells. A microarray analysis revealed the Wnt antagonist Dickopf-1 (DKK1) as a dysregulated gene in association with GATA6 knockdown, and direct binding of GATA6 to the DKK1 promoter was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift assays. Transient transfection of GATA6, but not mutant GATA6, into cancer cell lines led to decreased DKK1 mRNA expression and secretion of DKK1 protein into culture media. Forced overexpression of DKK1 antagonized the effects of GATA6 on Wnt signaling in pancreatic cancer cells. These findings illustrate that one mechanism by which GATA6 promotes pancreatic intraepithelial neoplasia is by virtue of its activation of canonical Wnt signaling via regulation of DKK1. AsPC1 and A13A cells were stably transfected with a lentivirus expressing mock shRNA or shRNA to GATA6. Each control/shRNA pair (total 4 samples) was analyzed by two-color microarray and the genes commonly dysregulated in both cell lines identified.
2011-02-10 | E-GEOD-27173 | biostudies-arrayexpress
Project description:We have previously described in mouse models that pancreas-specific deletion of Gata6 results in pancreas alterations by rendering pancreatic acinar cells in a non-fully differentiation state, and furthermore it accelerates tumor initiation and progression in a pro-tumorigenic context (KrasG12V expression). We aim to determine the sites where Gata6 binds at the genome-wide level in the pancreas to unveil why its loss leads to altered pancreatic function and enhanced tumor formation when coexpressed with KrasG12V.
2015-02-03 | GSE57090 | GEO
Project description:We report the global gene expression of mouse pancreatic cells in a pancreas-specific conditional knock-out mouse for Gata6, as compared with age-matched controls. Total RNA was extracted from the pancreas of 6-8 -week old mice of the two genotypes and analyzed. at this age, Gata6P-/- pancreata are histologically normal, but the acinar differentiation programme is already altered. we observe that loss of Gata6 causes the de-repression of ectopic non-pancreatic genes, as well as some genes involved in the mesenchymal programme.
2015-02-03 | GSE47536 | GEO
Project description:We report the global gene expression of mouse pancreatic cells in a pancreas-specific conditional knock-out mouse for Gata6, as compared with age-matched controls. Total RNA was extracted from the pancreas of 6-8 -week old mice of the two genotypes and analyzed. at this age, Gata6P-/- pancreata are histologically normal, but the acinar differentiation programme is already altered. we observe that loss of Gata6 causes the de-repression of ectopic non-pancreatic genes, as well as some genes involved in the mesenchymal programme. mRNA extracted from the pancreas of 4 controls and 4 Gata6P-/- mice was sequenced.
2015-02-03 | E-GEOD-47536 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by late diagnosis and treatment resistance. Recurrent genetic alterations in defined genes in association with perturbations of developmental cell signaling pathways have been associated with PDAC development and progression. Here, we show that GATA6 contributes to pancreatic carcinogenesis during the temporal progression of pancreatic intraepithelial neoplasia by virtue of Wnt pathway activation. GATA6 is recurrently amplified by both quantitative-PCR and fluorescent in-situ hybridization in human pancreatic intraepithelial neoplasia and in PDAC tissues, and GATA6 copy number is significantly correlated with overall patient survival. Forced overexpression of GATA6 in cancer cell lines enhanced cell proliferation and colony formation in soft agar in vitro and growth in vivo, as well as increased Wnt signaling. By contrast siRNA mediated knockdown of GATA6 led to corresponding decreases in these same parameters. The effects of GATA6 were found to be due to its ability to bind DNA, as forced overexpression of a DNA-binding mutant of GATA6 had no effects on cell growth in vitro or in vivo, nor did they affect Wnt signaling levels in these same cells. A microarray analysis revealed the Wnt antagonist Dickopf-1 (DKK1) as a dysregulated gene in association with GATA6 knockdown, and direct binding of GATA6 to the DKK1 promoter was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift assays. Transient transfection of GATA6, but not mutant GATA6, into cancer cell lines led to decreased DKK1 mRNA expression and secretion of DKK1 protein into culture media. Forced overexpression of DKK1 antagonized the effects of GATA6 on Wnt signaling in pancreatic cancer cells. These findings illustrate that one mechanism by which GATA6 promotes pancreatic intraepithelial neoplasia is by virtue of its activation of canonical Wnt signaling via regulation of DKK1.
2011-02-10 | GSE27173 | GEO
Project description:PURPOSE: To determine the impact of basal-like and classical subtypes in advanced PDAC and to explore GATA6 expression as a surrogate biomarker. EXPERIMENTAL DESIGN: Within the COMPASS trial patients proceeding to chemotherapy for advanced PDAC undergo tumour biopsy for RNA sequencing. Overall response rate (ORR) and overall survival (OS) were stratified by subtypes and according to chemotherapy received. Correlation of GATA6 with the subtypes using gene expression profiling, in situ hybridization (ISH) were explored. RESULTS: Between December 2015-May 2019, 195 patients (95%) had enough tissue for RNA sequencing; 39 (20%) were classified as basal-like and 156 (80%) as classical. RECIST response data were available for 157 patients; 29 basal-like and 128 classical where the ORR was 10% vs. 33% respectively (p=0.02). In patients with basal-like tumours treated with modified FOLFIRINOX (mFFX) (n=22) the progression rate was 60% compared to 15% in classical PDAC (p= 0.0002). Median OS in the intention to treat population (n=195) was 9.3 months for classical vs. 5.9 months for basal-like PDAC (HR 0.47 95% CI 0.32-0.69, p=0.0001). GATA6 expression by RNAseq highly correlated with the classifier (p<0.001) and ISH predicted the subtypes with sensitivity of 89% and specificity of 83%. In a multivariable analysis, GATA6 expression was prognostic (p=0.02). In exploratory analyses, basal-like tumours, could be identified by keratin 5, were more hypoxic and enriched for a T cell inflamed gene expression signature. CONCLUSIONS: The basal-like subtype is chemoresistant and can be distinguished from classical PDAC by GATA6 expression.
| EGAD00001006081 | EGA