title: Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer.
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.
authors: Department of Nephrology and Hypertension, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany.
authors: Steffen
authors: S
authors: Grampp
authors: Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors: James L
authors: JL
authors: Platt
authors: Department of Nephrology and Hypertension, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany.
authors: Victoria
authors: V
authors: Lauer
authors: Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors: Rafik
authors: 0000-0001-5549-7796
authors: R
authors: Salama
authors: Department of Nephrology and Hypertension, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany.|Department of Computer Science 9, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Cauerstraße 11, 91058 Erlangen, Germany.
authors: Franziska
authors: F
authors: Kranz
authors: Department of Nephrology and Hypertension, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany.
authors: Viviana K
authors: VK
authors: Neumann
authors: Department of Urology, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Krankenhausstraße 12, 91054 Erlangen, Germany.
authors: Sven
authors: S
authors: Wach
authors: Institute of Pathology, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Krankenhausstraße 8-10, 91054 Erlangen, Germany.
authors: Christine
authors: C
authors: Stöhr
authors: Institute of Pathology, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Krankenhausstraße 8-10, 91054 Erlangen, Germany.
authors: Arndt
authors: A
authors: Hartmann
authors: Department of Nephrology and Hypertension, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany.
authors: Kai-Uwe
authors: KU
authors: Eckardt
authors: Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors: Peter J
authors: 0000-0002-2853-806X
authors: PJ
authors: Ratcliffe
authors: Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors: David R
authors: DR
authors: Mole
authors: Department of Nephrology and Hypertension, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany.
authors: Johannes
authors: J
authors: Schödel
mesh_terms: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D002898:Chromosomes, Human, Pair 8; D021901:DNA, Intergenic / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C497396:ARNT protein, human; D002843:Chromatin; D021901:DNA, Intergenic; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C489427:MYC protein, human; C521123:PVT1 long-non-coding RNA, human; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human