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Transcription factors enriched in tumor-associated enhancers in VHL-deficient ccRCC

ABSTRACT: VHL loss is the most common genetic alteration event in ccRCC. We profiled histone modifications from VHL-deficient ccRCC primary tumors and cell lines. We show that ccRCCs exhibit a pervasive gain of enhancers around hypoxic and metabolic transcriptional targets. Motif analysis using HOMER revealed significant enrichment of AP-1, ETS, NFĸB and HIFα in tumor enhancers. We generated ChIP-seq binding data for c-Jun, ETS1, NFĸB, and P300, a histone acetyltransferase, in 786-O cells. ChIP-seq profiles of HIF2α and HIF1β in 786-O were already generated previously (GSE34871)

ORGANISM(S): Homo sapiens

PROVIDER: GSE86092 | GEO | 2017/08/22

SECONDARY ACCESSION(S): PRJNA340241

REPOSITORIES: GEO

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Next Generation Sequencing of 786-O-Ctrl and786-O-VHL Transcriptomes

Project description:Inactivation of the E3 ubiquitin ligase protein von Hippel-Lindau (VHL) is critical to clear cell renal cell carcinomas (ccRCC) and VHL syndrome. VHL loss leads to stabilization of hypoxia-inducible factor α (HIFα) and other substrate proteins, which may drive various tumor-promoting pathways. This process is likely reversible, because even in the highly aggressive human VHL-deficient ccRCC cell line 786-O, restoring VHL expression almost completely abolishes orthotopic tumor formation in immuno-deficient mice. This result highlights the potential of treating ccRCC by re-expressing VHL with gene therapy. However, there is inadequate understanding of the consequence of VHL restoration at the molecular level. Here, we reinstalled VHL expression in 786-O and performed transcriptome, proteome and ubiquitome profiling to assess the molecular impact.

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miRNA expression in primary renal carcinomas, subgrouped based on HIF1α expression

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Project description:VHL loss is the most common genetic alteration event in ccRCC. VHL loss stabilizes hypoxia-inducible factor-2 alpha (HIF2a). We compared the changes in transcriptomics profiles after VHL restoration or HIF2a siRNA knockdown in 786-O cells.

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Project description:To unravel the potential cooperative roles of oxygen-regulated signaling pathways; von Hippel-Lindau (VHL) tumor suppressor protein and hypoxia-inducible factor (HIF) transcription factors, we have generated mutant mice with; Vhlh, Vhlh/Hif1α, Vhlh/Hif2α and Vhlh/Hif1α/Hif2α gene alleles floxed. Subsequently primary kidney cells were isolated, cultured and infected with Adenoviruses bearing either Cre/GFP or GFP expression only. Agilent cDNA microarrays were utilized to compare the gene expression profiles of the kidney epithelial cells from aforementioned cell cultures to gain insight about the molecules and signaling pathways that drive aberrant cellular proliferation in clear cell renal cell carcinoma (ccRCC).

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cis-regulatory landscape in ccRCC [tissue]

Project description:VHL loss is the most common genetic alteration event in ccRCC, but its effect on epigenetic landscape has not been elucidated previously. By performing histone modifications (H3K27ac, H3K4me1, H3K4me3) from ccRCC cell lines, we describe the genome-wide cis-regulatory landscapes of VHL-deficient ccRCC tumors. We show that ccRCCs exhibit a pervasive gain of enhancers around hypoxic and metabolic transcriptional targets.

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cis-regulatory landscape in ccRCC [cell lines]

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786-O and 786-VHL in EMCV study

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