Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer
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 associ...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Nature Publishing Group
2016
|
| _version_ | 1797085903398633472 |
|---|---|
| author | Grampp, S Platt, J Lauer, V Salama, R Kranz, F Neumann, V Wach, S Stöhr, C Hartmann, A Eckardt, K Ratcliffe, P Mole, D Schödel, J |
| author_facet | Grampp, S Platt, J Lauer, V Salama, R Kranz, F Neumann, V Wach, S Stöhr, C Hartmann, A Eckardt, K Ratcliffe, P Mole, D Schödel, J |
| author_sort | Grampp, S |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T02:14:28Z |
| format | Journal article |
| id | oxford-uuid:a1c166e7-07a8-4a26-8eb8-0e65500dcd8c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:14:28Z |
| publishDate | 2016 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:a1c166e7-07a8-4a26-8eb8-0e65500dcd8c2022-03-27T02:15:28ZGenetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancerJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a1c166e7-07a8-4a26-8eb8-0e65500dcd8cEnglishSymplectic Elements at OxfordNature Publishing Group2016Grampp, SPlatt, JLauer, VSalama, RKranz, FNeumann, VWach, SStöhr, CHartmann, AEckardt, KRatcliffe, PMole, DSchödel, JClear 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. |
| spellingShingle | Grampp, S Platt, J Lauer, V Salama, R Kranz, F Neumann, V Wach, S Stöhr, C Hartmann, A Eckardt, K Ratcliffe, P Mole, D Schödel, J Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer |
| title | Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer |
| title_full | Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer |
| title_fullStr | Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer |
| title_full_unstemmed | Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer |
| title_short | Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer |
| title_sort | genetic variation at the 8q24 21 renal cancer susceptibility locus affects hif binding to a myc enhancer |
| work_keys_str_mv | AT grampps geneticvariationatthe8q2421renalcancersusceptibilitylocusaffectshifbindingtoamycenhancer AT plattj geneticvariationatthe8q2421renalcancersusceptibilitylocusaffectshifbindingtoamycenhancer AT lauerv geneticvariationatthe8q2421renalcancersusceptibilitylocusaffectshifbindingtoamycenhancer AT salamar geneticvariationatthe8q2421renalcancersusceptibilitylocusaffectshifbindingtoamycenhancer AT kranzf geneticvariationatthe8q2421renalcancersusceptibilitylocusaffectshifbindingtoamycenhancer AT neumannv geneticvariationatthe8q2421renalcancersusceptibilitylocusaffectshifbindingtoamycenhancer AT wachs geneticvariationatthe8q2421renalcancersusceptibilitylocusaffectshifbindingtoamycenhancer AT stohrc geneticvariationatthe8q2421renalcancersusceptibilitylocusaffectshifbindingtoamycenhancer AT hartmanna geneticvariationatthe8q2421renalcancersusceptibilitylocusaffectshifbindingtoamycenhancer AT eckardtk geneticvariationatthe8q2421renalcancersusceptibilitylocusaffectshifbindingtoamycenhancer AT ratcliffep geneticvariationatthe8q2421renalcancersusceptibilitylocusaffectshifbindingtoamycenhancer AT moled geneticvariationatthe8q2421renalcancersusceptibilitylocusaffectshifbindingtoamycenhancer AT schodelj geneticvariationatthe8q2421renalcancersusceptibilitylocusaffectshifbindingtoamycenhancer |