Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer

Steffen Grampp, James L. Platt, Victoria Lauer, Rafik Salama, Franziska Kranz, Viviana K. Neumann, Sven Wach, Christine Stöhr, Arndt Hartmann, Kai-Uwe Eckardt, Peter J. Ratcliffe, David R. Mole and Johannes Schödel ()
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Steffen Grampp: Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg
James L. Platt: Henry Wellcome Building for Molecular Physiology, University of Oxford
Victoria Lauer: Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg
Rafik Salama: Henry Wellcome Building for Molecular Physiology, University of Oxford
Franziska Kranz: Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg
Viviana K. Neumann: Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg
Sven Wach: Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg
Christine Stöhr: Institute of Pathology, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg
Arndt Hartmann: Institute of Pathology, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg
Kai-Uwe Eckardt: Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg
Peter J. Ratcliffe: Henry Wellcome Building for Molecular Physiology, University of Oxford
David R. Mole: Henry Wellcome Building for Molecular Physiology, University of Oxford
Johannes Schödel: Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract Clear cell renal cell carcinoma (ccRCC) is characterized by loss of function of the von Hippel–Lindau tumour suppressor (VHL) and unrestrained activation of hypoxia-inducible transcription factors (HIFs). Genetic and epigenetic determinants have an impact on HIF pathways. A recent genome-wide association study on renal cancer susceptibility identified single-nucleotide polymorphisms (SNPs) in an intergenic region located between the oncogenes MYC and PVT1. Here using assays of chromatin conformation, allele-specific chromatin immunoprecipitation 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 HIF binding to the enhancer. These findings provide further evidence that genetic variation at HIF-binding sites modulates the oncogenic transcriptional output of the VHL–HIF axis and provide a functional explanation for the disease-associated effects of SNPs in ccRCC.

Date: 2016
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DOI: 10.1038/ncomms13183

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