Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Myc and PI3-k induced gene expression in RWPE1

ABSTRACT: Analysis of transcriptional changes during Myc or PI3K induced oncogenic transformation in RWPE1 cells (benign prostate epithelial cell line). The aim of the present study was to identify key epigenetic gene silencing events that occur during the oncogenic transformation events, hence emphasis was placed on downregulated genes. Results provide important information on which are the tumor suppressive pathways or genes that will be epigenetically silenced by during Myc or PI3K induced oncogenic transformation. Total RNA obtained from oncogenic transformed RWPE1 cells which were either overexpressing Myc or constitutive active mutant of PI3K (E545K) as compared to RWPE1 cells expressing the empty vector control PMN.

ORGANISM(S): Homo sapiens

SUBMITTER: Zhen Ning Wee

PROVIDER: E-GEOD-43686 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

EZH2-mediated inactivation of IFN-γ-JAK-STAT1 signaling is an effective therapeutic target in MYC-driven prostate cancer.

Wee Zhen Ning ZN Li Zhimei Z Lee Puay Leng PL Lee Shuet Theng ST Lim Yoon Pin YP Yu Qiang Q

Cell reports 20140619 1

Although small-molecule targeting of EZH2 appears to be effective in lymphomas carrying EZH2 activating mutations, finding similar approaches to target EZH2-overexpressing epithelial tumors remains challenging. In MYC-driven, but not PI3K-driven prostate cancer, we show that interferon-γ receptor 1 (IFNGR1) is directly repressed by EZH2 in a MYC-dependent manner and is downregulated in a subset of metastatic prostate cancers. EZH2 knockdown restored the expression of IFNGR1 and, when combined wi ...[more]

PMID: 24953652

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Project description:Proprionibacterium acnes is a Gram positive bacterium found ubiquitously on human skin, where it is typically considered to assume a commensal relationship with its host. However, it is also closely associated with the skin condition acne vulgaris. More controversially, it has a postulated involvement in infections of implanted prosthetic devices and has been isolated from malignant prostate tissues. The role of P. acnes in these pathologies remains undetermined, although both bacterial and host factors are implicated. By microarray analysis, we have identified fundamental differences in the global transcriptional profiles of keratinocyte and prostate cells to P. acnes infection. Notably, P. acnes infection of the keratinocyte cell line, HaCaT, elicited a robust, but acute inflammatory response. By contrast, the inflammatory response of the prostate cell line, RWPE1, was delayed and persisted for longer times. Immunofluorescence and electron microscopy revealed higher numbers of internalized P. acnes bacteria in RWPE1 cells, which could still be detected intracellularly three weeks post infection. This contrasted with HaCaT cells, which P. acnes largely failed to invade. Moreover, P. acnes induced a delayed, sustained activation of NFM-NM-:B in RWPE1 cells, which was absent in HaCaT cells. Further characterization of the host-cell response to infection revealed that the intermediate filament protein, vimentin, was a key determinant of P. acnes invasion, persistence and inflammatory profile in RWPE1 cells. siRNA mediated knock down of vimentin in RWPE1 cells attenuated bacterial invasion and the inflammatory response to infection; similarly, overexpression of vimentin in HaCaT cells increased bacterial invasion. We conclude that vimentin-dependent host-tissue tropism, in part, determines P. acnes invasion and inflammatory capacity. This could contribute to P. acnes pathology at non-skin infection sites. Microarray experiments were performed as dual-color hybridizations. In order to compensate specific effects of the dyes and to ensure statistically relevant data analysis, a color-swap dye-reversal was performed.

Project description:Emerging evidence suggests that chromatin adopts a non-random three-dimensional (3D) topology and that the organization of genes into structural hubs and domains affects their transcriptional status. How chromatin conformation changes in diseases such as cancer is poorly understood. Moreover, how oncogenic transcription factors, which bind to thousands of sites across the genome, influence gene regulation by globally altering the topology of chromatin requires further investigation. To address these questions, we performed unbiased high-resolution mapping of intra- and inter-chromosome interactions upon over-expression of ERG, an oncogenic transcription factor frequently over-expressed in prostate cancer as a result of a gene fusion. By integrating data from genome-wide chromosome conformation capture (Hi-C), ERG binding and gene expression, we demonstrate that oncogenic transcription factor over-expression is associated with global, reproducible and functionally coherent changes in chromatin organization. The results presented here have broader implications, as genomic alterations in other cancer types frequently give rise to aberrant transcription factor expression e.g., EWS-FLI1, c-Myc, n-Myc, PML-RARα. We used stable isogenic, normal benign prostate epithelial cell lines (RWPE1) that differ with respect to ERG3 over-expression. To test whether ERG over-expression is associated with global changes in chromatin structure, we performed unbiased chromatin interaction mapping using the Hi-C technique from both RWPE1-ERG and RWPE1-GFP cells, with biological replicates. Successful fill-in and ligation were determined as previously reported by testing for a known interaction between two distant genomic loci located on chromosome 6. The Hi-C libraries were paired-end sequenced using an Illumina GAIIx platform. Following alignment to the human genome (hg18) and filtering to remove un-ligated and self-ligated DNA, we identified intra-chromosomal (or cis-) and inter-chromosomal (or trans-) interactions in both RWPE1 cell lines. To characterize ERG binding and ERG-mediated gene expression changes in these cells, we performed chromatin-immunoprecipitation combined with high-throughput sequencing (ChIP-seq) and RNA sequencing (RNA-seq). ERG was bound to 6,398 sites in RPWE1-ERG cells. Based on paired-end RNA-seq data from both cell lines, 1,266 genes were differentially expressed between RWPE1-ERG and RWPE1-GFP cell lines.

Dataset Information

Myc and PI3-k induced gene expression in RWPE1

Publications

EZH2-mediated inactivation of IFN-γ-JAK-STAT1 signaling is an effective therapeutic target in MYC-driven prostate cancer.

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