Unbiased analysis of potential targets of breast cancer susceptibility loci by Capture Hi-C.
Unbiased analysis of potential targets of breast cancer susceptibility loci by Capture Hi-C.
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DOI：
10.1101/gr.175034.114
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发表时间：
2014-11
期刊：
影响因子：
7
通讯作者：
Fletcher O
中科院分区：
文献类型：
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作者：
Dryden NH;Broome LR;Dudbridge F;Johnson N;Orr N;Schoenfelder S;Nagano T;Andrews S;Wingett S;Kozarewa I;Assiotis I;Fenwick K;Maguire SL;Campbell J;Natrajan R;Lambros M;Perrakis E;Ashworth A;Fraser P;Fletcher O
全基因组关联研究已经确定了70多种与乳腺癌风险相关的常见变异。这些变异大多数映射到非蛋白质编码区，一些映射到基因沙漠，数百个碱基缺乏蛋白质编码基因的区域。我们假设基因沙漠中含有远程调控元件，这些元件可以与靶基因物理相互作用以影响其表达。为了验证这一点，我们开发了Capture Hi-C (CHi-C)，通过将序列捕获步骤纳入Hi-C协议，可以对基因组的目标区域进行高分辨率分析。我们使用CHi-C研究了定位于2q35、8q24.21和9q31.2的三个乳腺癌基因沙漠的远程相互作用。我们确定了捕获区域内假定的调控元件（“诱饵片段”）与“目标”（包括蛋白质编码基因和长非编码（lnc） rna）之间的相互作用峰，距离为6.6 kb至2.6 Mb。目标蛋白质编码基因为IGFBP5， KLF4， NSMCE2和MYC；靶lncrna包括DIRC3、PVT1和CCDC26。对于一个基因沙漠，我们能够定义两个snp (rs12613955和rs4442975)，它们与已发表的风险变异高度相关，并且位于相互作用峰的诱饵端。体内ChIP-qPCR数据显示，其中一个位点rs4442975影响FOXA1的结合，并暗示该SNP可能是一个功能性变异。
Genome-wide association studies have identified more than 70 common variants that are associated with breast cancer risk. Most of these variants map to non-protein-coding regions and several map to gene deserts, regions of several hundred kilobases lacking protein-coding genes. We hypothesized that gene deserts harbor long-range regulatory elements that can physically interact with target genes to influence their expression. To test this, we developed Capture Hi-C (CHi-C), which, by incorporating a sequence capture step into a Hi-C protocol, allows high-resolution analysis of targeted regions of the genome. We used CHi-C to investigate long-range interactions at three breast cancer gene deserts mapping to 2q35, 8q24.21, and 9q31.2. We identified interaction peaks between putative regulatory elements (“bait fragments”) within the captured regions and “targets” that included both protein-coding genes and long noncoding (lnc) RNAs over distances of 6.6 kb to 2.6 Mb. Target protein-coding genes were IGFBP5, KLF4, NSMCE2, and MYC; and target lncRNAs included DIRC3, PVT1, and CCDC26. For one gene desert, we were able to define two SNPs (rs12613955 and rs4442975) that were highly correlated with the published risk variant and that mapped within the bait end of an interaction peak. In vivo ChIP-qPCR data show that one of these, rs4442975, affects the binding of FOXA1 and implicate this SNP as a putative functional variant.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
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影响因子：
8.8
作者：
Forozan, F;Veldman, R;Ammerman, CA;Parsa, NZ;Kallioniemi, A;Kallioniemi, OP;Ethier, SP
通讯作者：
Ethier, SP
DOI：
10.1038/nrg3454
发表时间：
2013-06
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
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影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M