Quadruplex-single nucleotide polymorphisms (Quad-SNP) influence gene expression difference among individuals.
Quadruplex-single nucleotide polymorphisms (Quad-SNP) influence gene expression difference among individuals.
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DOI：
10.1093/nar/gkr1258
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发表时间：
2012-05
影响因子：
14.9
通讯作者：
Chowdhury S
中科院分区：
文献类型：
--
作者：
Baral A;Kumar P;Halder R;Mani P;Yadav VK;Singh A;Das SK;Chowdhury S
非规范的鸟嘌呤四链体结构不仅占主导地位，而且在细菌和哺乳动物启动子中是保守的。此外，最近的研究结果直接涉及四链体结构的转录。这些都认为结构基序的内在作用，从而证明单核苷酸多态性（SNP），损害四链体结构可能会影响功能。为了验证这一点，我们分析了四链体基序内的SNP（Quad-SNP）和代表超过14500种基因型的四个群体（HapMap）中270个个体的基因表达。研究结果显示，在个体中，四链SNPs与相应基因的表达之间存在显著关联（P < 0.0001）。此外，对从1000个人类基因组的群体规模测序中获得的Quad-SNPs的分析显示了对结构基序改变的相对选择偏倚。为了直接测试四链体-SNP-转录连接，我们使用RPS 3启动子构建了报告系统-注意到“四链体-不稳定”与“四链体-完整”启动子中启动子活性的显著差异。作为进一步的测试，我们将四链体基序或其破坏的对应物掺入合成启动子报告构建体中。四链体基序，而不是破坏基序，增强了不同来源的人类细胞系的转录。总之，这些研究结果建立了直接支持四链体介导的转录，并建议四链体-SNP可能发挥重要作用，在机械上理解个体之间的基因表达的变化。
Non-canonical guanine quadruplex structures are not only predominant but also conserved among bacterial and mammalian promoters. Moreover recent findings directly implicate quadruplex structures in transcription. These argue for an intrinsic role of the structural motif and thereby posit that single nucleotide polymorphisms (SNP) that compromise the quadruplex architecture could influence function. To test this, we analysed SNPs within quadruplex motifs (Quad-SNP) and gene expression in 270 individuals across four populations (HapMap) representing more than 14 500 genotypes. Findings reveal significant association between quadruplex-SNPs and expression of the corresponding gene in individuals (P < 0.0001). Furthermore, analysis of Quad-SNPs obtained from population-scale sequencing of 1000 human genomes showed relative selection bias against alteration of the structural motif. To directly test the quadruplex-SNP-transcription connection, we constructed a reporter system using the RPS3 promoter—remarkable difference in promoter activity in the ‘quadruplex-destabilized’ versus ‘quadruplex-intact’ promoter was noticed. As a further test, we incorporated a quadruplex motif or its disrupted counterpart within a synthetic promoter reporter construct. The quadruplex motif, and not the disrupted-motif, enhanced transcription in human cell lines of different origin. Together, these findings build direct support for quadruplex-mediated transcription and suggest quadruplex-SNPs may play significant role in mechanistically understanding variations in gene expression among individuals.
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影响因子：
64.8
作者：
Gibbs, RA;Belmont, JW;Tanaka, T
通讯作者：
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