Journal article
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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 1.2MB, Terms of use)
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- Publisher copy:
- 10.1038/ncomms13183
Authors
+ Else Kro¨ner-Fresenius Exzellenzstipendium
More from this funder
- Funding agency for:
- Schödel, J
- Grant:
- 2014_EKES.11
- Publisher:
- Nature Publishing Group
- Journal:
- Nature Communications More from this journal
- Volume:
- 7
- Pages:
- 13183
- Publication date:
- 2016-10-24
- Acceptance date:
- 2016-09-08
- DOI:
- EISSN:
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2041-1723
- Language:
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English
- Keywords:
- Pubs id:
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pubs:655091
- UUID:
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uuid:a1c166e7-07a8-4a26-8eb8-0e65500dcd8c
- Local pid:
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pubs:655091
- Source identifiers:
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655091
- Deposit date:
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2016-11-02
Terms of use
- Copyright holder:
- © 2016 Grampp, et al
- Copyright date:
- 2016
- Notes:
- © 2016 the Authors. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
- Licence:
- CC Attribution (CC BY)
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