Functional analysis of APOE locus genetic variation implicates regional enhancers in the regulation of both TOMM40 and APOE.
Functional analysis of APOE locus genetic variation implicates regional enhancers in the regulation of both TOMM40 and APOE.
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APOE 位点遗传变异的功能分析表明区域增强子参与 TOMM40 和 APOE 的调节。
DOI：
10.1038/jhg.2011.123
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发表时间：
2012-01
影响因子：
3.5
通讯作者：
中科院分区：
文献类型：
--
作者：
载脂蛋白E基因（APOE）位点内的遗传变异与迟发性阿尔茨海默病风险和数量性状以及多种组织中的apoE表达相关。本研究的目的是探讨APOE位点顺式调控元件增强子区域的遗传变异对区域基因启动子活性的影响。在3种人细胞系中，评价了含有APOE基因座基因启动子单倍型的荧光素酶报告基因构建体; APOE、APOC 1和TOMM 40，以及区域推定增强子; TOMM 40 IVS 2 -4、TOMM 40 IVS 6 poly-T，以及先前描述的增强子; ME 1或BCR对荧光素酶活性的影响。本研究结果表明，在SHSY 5 Y细胞中，APOE启动子受TOMM 40 IVS 2 -4和ME 1的显著影响，TOMM 40启动子受TOMM 40 IVS 6 poly-T、ME 1和BCR的显著影响。在HepG 2细胞中，TOMM 40启动子受到所有四种增强子的显著影响，而APOE启动子不受任何增强子的影响。这项研究的主要新发现是，多个APOE基因座顺式元件影响APOE和TOMM 40启动子的活性，根据单倍型和细胞类型表明，一个复杂的转录调控结构调节区域表达。
Genetic variation within the apolipoprotein E gene (APOE) locus is associated with late-onset Alzheimer's disease risk and quantitative traits as well as apoE expression in multiple tissues. The aim of this investigation was to explore the influence of APOE locus cis-regulatory element enhancer region genetic variation on regional gene promoter activity. Luciferase reporter constructs containing haplotypes of APOE locus gene promoters; APOE, APOC1, and TOMM40, and regional putative enhancers; TOMM40 IVS2-4, TOMM40 IVS6 poly-T, as well as previously described enhancers; ME1, or BCR, were evaluated for their effects on luciferase activity in 3 human cell lines. Results of this investigation demonstrate that in SHSY5Y cells, the APOE promoter is significantly influenced by the TOMM40 IVS2-4 and ME1 and the TOMM40 promoter is significantly influenced by the TOMM40 IVS6 poly-T, ME1 and BCR. In HepG2 cells, theTOMM40 promoter is significantly influenced by all four enhancers, whereas the APOE promoter is not influenced by any of the enhancers. The main novel finding of this investigation was that multiple APOE locus cis-elements influence both APOE and TOMM40 promoter activity according to haplotype and cell type suggesting that a complex transcriptional regulatory structure modulates regional expression.
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影响因子：
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通讯作者：
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