nature-genetic201211-1

来自加拿大多伦多大学的Mathieu Lupien、美国达特茅斯医学院的Jason Moore及其同事发现乳腺癌风险相关的单核苷酸多态性(SNPs)通常会破坏转录因子FOXA1与染色质的互作,从而直接影响下游的基因表达。相关的研究论文于9月23日在线发表在《Nature Genetics》期刊上。

-2012年11月《自然-遗传》

中文翻译


【题目】乳腺癌风险相关的SNPs调节染色质与FOXA1因子的亲和性

【译文】全基因组关联研究(GWAS)已经鉴定到数以千计的、与人类性状和疾病发病相关的单核苷酸多态性(SNPs)。但是由于绝大多数已鉴定的SNPs都定位于染色体组的非编码区域,所以SNPs促进疾病风险的相关机制就显得难以被攻克。我们借助一种结合顺反子组学、表观基因组学和基因型归责的新方法,对乳腺癌细胞基因组的非编码区域进行了注释,系统鉴定到与乳腺癌风险相关的SNPs功能性质。我们的结果表明乳腺癌风险相关的SNPs,以癌症和细胞类型特异性方式,在FOXA1和ESR1的顺反子组和单甲基化的组蛋白H3赖氨酸4(H3K4me1)的表观基因组上十分丰富。此外,大多数风险相关的SNPs在远端调控元件上调节FOXA1与染色质的亲和性,因此促进等位基因特异性的基因表达,例如,在16q12.1风险位点内,rs4784227 SNP对TOX3基因的影响。

英文原稿


[Title]: Breast cancer risk–associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression

[Authors]: Richard Cowper-Sal·lari, Xiaoyang Zhang, Jason B Wright, Swneke D Bailey, Michael D Cole, Jerome Eeckhoute, Jason H Moore & Mathieu Lupien

[Abstract]: Genome-wide association studies (GWAS) have identified thousands of SNPs that are associated with human traits and diseases. But, because the vast majority of these SNPs are located in non-coding regions of the genome, the mechanisms by which they promote disease risk have remained elusive. Employing a new methodology that combines cistromics, epigenomics and genotype imputation, we annotate the non-coding regions of the genome in breast cancer cells and systematically identify the functional nature of SNPs associated with breast cancer risk. Our results show that breast cancer risk–associated SNPs are enriched in the cistromes of FOXA1 and ESR1 and the epigenome of histone H3 lysine 4 monomethylation (H3K4me1) in a cancer- and cell type–specific manner. Furthermore, the majority of the risk-associated SNPs modulate the affinity of chromatin for FOXA1 at distal regulatory elements, thereby resulting in allele-specific gene expression, which is exemplified by the effect of the rs4784227 SNP on the TOX3 gene within the 16q12.1 risk locus.

原文地址

http://www.nature.com/ng/journal/v44/n11/abs/ng.2416.html

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