A renal cancer-associated, renal tubule-specific, HIF-binding enhancer of oncogenic MYC and PVT1 expression

Clear cell renal cell carcinoma is characterized by loss of function of the von Hippel-Lindau tumor suppressor gene (VHL) and unrestrained activation of hypoxia inducible transcription factors (HIF). Genetic and epigenetic determinants can impact on HIF pathways. A recent genome-wide association study identified single nucleotide polymorphisms (SNPs) in an intergenic region on chromosome 8 that modify the risk of developing renal cancer. The SNPs are located in a putative regulatory region between the oncogenes MYC and PVT1. Using capture C assay and genome editing we show that HIF-binding to this regulatory element is necessary to trans-activate MYC and PVT1 expression specifically in cells of renal tubular origins. Moreover, we demonstrate that the risk associated polymorphisms increase chromatin accessibility and activity as well as binding of HIF to the enhancer. These findings further strengthen the hypothesis that genetic variation at HIF-binding sites modulates the oncogenic transcriptional output of the VHL-HIF axis and provide a functional explanation for disease associated effects of SNPs in ccRCC. Overall design: We utilized Capture-C with a capture region that incorporates the SNP of interest. Studying the interactions made between this and the rest of the genome.