Identification of polymorphic antioxidant response elements in the human genome
Identification of polymorphic antioxidant response elements in the human genome
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DOI：
10.1093/hmg/ddm066
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发表时间：
2007-05-15
影响因子：
3.5
通讯作者：
Bell, Douglas A.
中科院分区：
文献类型：
--
作者：
Wang, Xuting;Tomso, Daniel J.;Bell, Douglas A.
转录因子结合位点（TFBS）的单核苷酸多态性（SNPs）可能影响转录因子的结合，导致基因表达和表型的差异，从而影响环境暴露的易感性。我们开发了一个集成的计算系统，用于发现人类基因组中TFBS中的功能SNP，并预测它们对靶基因表达的影响。在这个系统中，我们（i）从实验发现的TFBS集合中构建位置权重矩阵（PWM）;（ii）使用PWM预测SNP序列中的TFBS，并将SNP定位到基因的上游区域;（iii）通过系统发育足迹来检查推定的TFBS的进化保守性;（iv）基于来自其中感兴趣的转录因子缺失或过表达的组织的微阵列表达谱对候选SNP进行优先排序，以及（v）最后，分析SNP基因型与基因表达表型的关联。我们的系统的应用程序已经过测试，以确定在抗氧化反应元件（ARE），顺式作用增强子序列中发现的许多基因的启动子区域编码抗氧化剂和II期解毒酶/蛋白质的功能多态性。在氧化应激反应中，转录因子NRF 2（核因子红细胞衍生2样2）结合战神，介导其应答基因的转录激活，并调节体内抗氧化损伤的防御机制。使用我们的新的计算工具，我们已经确定了一组多态性战神与功能的证据，显示我们的系统的效用，以指导进一步的实验验证基因组序列变异，可能是有用的识别高风险的个人。
Single nucleotide polymorphisms (SNPs) in transcription factor binding sites (TFBSs) may affect the binding of transcription factors, lead to differences in gene expression and phenotypes and therefore affect susceptibility to environmental exposure. We developed an integrated computational system for discovering functional SNPs in TFBSs in the human genome and predicting their impact on the expression of target genes. In this system, we (i) construct a position weight matrix (PWM) from a collection of experimentally discovered TFBSs; (ii) predict TFBSs in SNP sequences using the PWM and map SNPs to the upstream regions of genes; (iii) examine the evolutionary conservation of putative TFBSs by phylogenetic footprinting; (iv) prioritize candidate SNPs based on microarray expression profiles from tissues in which the transcription factor of interest is either deleted or over-expressed and (v) finally, analyze association of SNP genotypes with gene expression phenotypes. The application of our system has been tested to identify functional polymorphisms in the antioxidant response element (ARE), a cis-acting enhancer sequence found in the promoter region of many genes that encode antioxidant and Phase II detoxification enzymes/proteins. In response to oxidative stress, the transcription factor NRF2 (nuclear factor erythroid-derived 2-like 2) binds to AREs, mediating transcriptional activation of its responsive genes and modulating in vivo defense mechanisms against oxidative damage. Using our novel computational tools, we have identified a set of polymorphic AREs with functional evidence, showing the utility of our system to direct further experimental validation of genomic sequence variations that could be useful for identifying high-risk individuals.