Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression.
Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression.
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DOI：
10.1038/ng.2416
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发表时间：
2012-11
期刊：
影响因子：
30.8
通讯作者：
Lupien M
中科院分区：
文献类型：
--
作者：
Cowper-Sal lari R;Zhang X;Wright JB;Bailey SD;Cole MD;Eeckhoute J;Moore JH;Lupien M
全基因组关联研究（GWASs）已经确定了数千个与人类性状和疾病相关的单核苷酸多态性（SNP）。但是，由于绝大多数SNPs位于基因组的非编码区，因此其风险促进机制难以理解。采用一种新的方法相结合的顺式，表观基因组学和基因型插补，我们注释的非编码区的基因组在乳腺癌细胞和系统地确定功能性的SNPs与乳腺癌的风险。我们的研究结果表明，乳腺癌风险相关的SNP在FOXA 1和ESR1的顺式组和H3K4me1的表观基因组中以癌症和细胞类型特异性的方式富集。此外，大多数这些风险相关的SNP在远端调控元件调节染色质对FOXA 1的亲和力，这导致等位基因特异性基因表达，例如rs4784227 SNP对16q12.1风险基因座内发现的TOX3基因的影响。
Genome-wide association studies (GWASs) have identified thousands of single nucleotide polymorphisms (SNPs) associated with human traits and diseases. But because the vast majority of these SNPs are located in the noncoding regions of the genome their risk promoting mechanisms are elusive. Employing a new methodology combining cistromics, epigenomics and genotype imputation we annotate the noncoding regions of the genome in breast cancer cells and systematically identify the functional nature of SNPs associated with breast cancer risk. Our results demonstrate that breast cancer risk-associated SNPs are enriched in the cistromes of FOXA1 and ESR1 and the epigenome of H3K4me1 in a cancer and cell-type-specific manner. Furthermore, the majority of these risk-associated SNPs modulate the affinity of chromatin for FOXA1 at distal regulatory elements, which results in allele-specific gene expression, exemplified by the effect of the rs4784227 SNP on the TOX3 gene found within the 16q12.1 risk locus.
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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.
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Bernstein, Bradley E.
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30.8
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Liu, X. Shirley
影响因子：
64.8
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Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
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Ren, Bing
影响因子：
4.5
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Long J;Cai Q;Shu XO;Qu S;Li C;Zheng Y;Gu K;Wang W;Xiang YB;Cheng J;Chen K;Zhang L;Zheng H;Shen CY;Huang CS;Hou MF;Shen H;Hu Z;Wang F;Deming SL;Kelley MC;Shrubsole MJ;Khoo US;Chan KY;Chan SY;Haiman CA;Henderson BE;Le Marchand L;Iwasaki M;Kasuga Y;Tsugane S;Matsuo K;Tajima K;Iwata H;Huang B;Shi J;Li G;Wen W;Gao YT;Lu W;Zheng W
通讯作者：
Zheng W
影响因子：
30.8
作者：
Carroll, Jason S.;Meyer, Clifford A.;Brown, Myles
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Brown, Myles