Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer.
Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer.
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8q24.21肾癌易感性基因座的遗传变异会影响HIF与MYC增强子的结合。
DOI：
10.1038/ncomms13183
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发表时间：
2016-10-24
影响因子：
16.6
通讯作者：
Schoedel, Johannes
中科院分区：
文献类型：
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作者：
Grampp, Steffen;Platt, James L.;Lauer, Victoria;Salama, Rafik;Kranz, Franziska;Neumann, Viviana K.;Wach, Sven;Stoehr, Christine;Hartmann, Arndt;Eckardt, Kai-Uwe;Ratcliffe, Peter J.;Mole, David R.;Schoedel, Johannes
透明细胞肾细胞癌 (ccRCC) 的特点是 von Hippel-Lindau 肿瘤抑制因子 (VHL) 功能丧失和缺氧诱导转录因子 (HIF) 不受限制的激活。遗传和表观遗传决定因素对 HIF 通路有影响。最近一项关于肾癌易感性的全基因组关联研究发现，位于癌基因 MYC 和 PVT1 之间的基因间区域存在单核苷酸多态性 (SNP)。在这里，通过染色质构象、等位基因特异性染色质免疫沉淀和基因组编辑的测定，我们表明 HIF 与该调节元件的结合对于反式激活 MYC 和 PVT1 表达（特别是在肾小管起源的细胞中）是必需的。此外，我们证明与风险相关的多态性增加了染色质的可及性和活性以及 HIF 与增强子的结合。这些发现提供了进一步的证据，证明 HIF 结合位点的遗传变异调节 VHL-HIF 轴的致癌转录输出，并为 ccRCC 中 SNP 的疾病相关效应提供功能解释。全基因组关联研究已经确定了多个与患肾癌风险相关的基因座。在这里，作者表明这些基因座之一会产生开放染色质，从而增强 HIF 的结合以及 HIF 介导的 MYC 反式激活。
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. Genome-wide association studies have identified multiple loci associated with the risk of developing renal cancer. Here, the authors show that one of these loci generates open chromatin, which enhances the binding of HIF and HIF-mediated transactivation of MYC.
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影响因子：
30.8
作者：
通讯作者：
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影响因子：
30.8
作者：
Kiemeney LA;Thorlacius S;Sulem P;Geller F;Aben KK;Stacey SN;Gudmundsson J;Jakobsdottir M;Bergthorsson JT;Sigurdsson A;Blondal T;Witjes JA;Vermeulen SH;Hulsbergen-van de Kaa CA;Swinkels DW;Ploeg M;Cornel EB;Vergunst H;Thorgeirsson TE;Gudbjartsson D;Gudjonsson SA;Thorleifsson G;Kristinsson KT;Mouy M;Snorradottir S;Placidi D;Campagna M;Arici C;Koppova K;Gurzau E;Rudnai P;Kellen E;Polidoro S;Guarrera S;Sacerdote C;Sanchez M;Saez B;Valdivia G;Ryk C;de Verdier P;Lindblom A;Golka K;Bishop DT;Knowles MA;Nikulasson S;Petursdottir V;Jonsson E;Geirsson G;Kristjansson B;Mayordomo JI;Steineck G;Porru S;Buntinx F;Zeegers MP;Fletcher T;Kumar R;Matullo G;Vineis P;Kiltie AE;Gulcher JR;Thorsteinsdottir U;Kong A;Rafnar T;Stefansson K
通讯作者：
Stefansson K
影响因子：
64.8
作者：
通讯作者：
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影响因子：
7.7
作者：
Choudhry, Hani;Schoedel, Johannes;Oikonomopoulos, Spyros;Camps, Carme;Grampp, Steffen;Harris, Adrian L.;Ratcliffe, Peter J.;Ragoussis, Jiannis;Mole, David R.
通讯作者：
Mole, David R.
影响因子：
30.8
作者：
通讯作者：
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