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

Journal article


Publication Details

Author(s): Grampp S, Platt JL, Lauer V, Salama R, Kranz F, Neumann VK, Wach S, Stoehr C, Hartmann A, Eckardt KU, Ratcliffe PJ, Mole DR, Schoedel J
Journal: Nature Communications
Publication year: 2016
Volume: 7
Pages range: 13183
ISSN: 2041-1723


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.



FAU Authors / FAU Editors

Eckardt, Kai-Uwe Prof. Dr. med.
Lehrstuhl für Innere Medizin IV
Hartmann, Arndt Prof. Dr. med.
Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie
Kranz, Franziska
Lehrstuhl für Informatik 9 (Graphische Datenverarbeitung)
Lauer, Victoria
Medizinische Klinik 4 - Nephrologie und Hypertensiologie


How to cite

APA:
Grampp, S., Platt, J.L., Lauer, V., Salama, R., Kranz, F., Neumann, V.K.,... Schoedel, J. (2016). Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer. Nature Communications, 7, 13183. https://dx.doi.org/10.1038/ncomms13183

MLA:
Grampp, Steffen, et al. "Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer." Nature Communications 7 (2016): 13183.

BibTeX: 

Last updated on 2018-19-04 at 03:50