Regulation of human CYP11B1 and CYP11B2 promoters by transposable elements and conserved cis elements
Regulation of human CYP11B1 and CYP11B2 promoters by transposable elements and conserved cis elements
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DOI：
10.1016/j.steroids.2011.10.010
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发表时间：
2012-01-01
期刊：
影响因子：
2.7
通讯作者：
Li, Lih-Ann
中科院分区：
文献类型：
--
作者：
Cheng, Li-Chuan;Pai, Tun-Wen;Li, Lih-Ann
CYP 11B 1和CYP 11B 2分别负责皮质醇和醛固酮合成的最后步骤，被认为是具有独特启动子的重复基因。我们的序列分析发现，这两个基因有很大的同源性，在近端上游区域，但插入的Alu和L1元件驱动启动子分歧。每个CYP 11B启动子包含两个嵌入截短的L1元件中的Alu元件，将L1断裂成三个不连接的片段。Alu在这两个基因中起增强子的作用，而与方向和拷贝数无关。在SV 40启动子上游插入Alu也提高了启动子活性。然而，Alu对CYP 11B 1的作用被插入在第一个和保守的近端上游区域之间的第二个L1元件（CYP 11B 1-L1.2）阻断。虽然CYP 11B 1-L1.2是5 '截短的并且缺乏功能性ORF，但是用荧光基因替换它证明该元件可以从CYP 11B 1核心启动子以相反的方向转录，并且与CYP 11B 1相比幅度较小。CYP 11B 1-L1.2的缺失大大提高了CYP 11B 1启动子的活性，并恢复了Alu的增强作用。在近端核心启动子中保守的Ad 5和SF-1结合元件在两个基因的基础表达中起作用。Ad 5位点的突变将启动子活性降低到最低水平。ERR α是在基础表达期间与Ad 5相互作用的转录因子。这两个基因的核心启动子在小鼠和大鼠中也是保守的，尽管啮齿动物Cyp 11b 1启动子中对应于cre，Ad 5和SF-1的位点偏离了共识。(C)2011 Elsevier Inc. All rights reserved.
CYP11B1 and CYP11B2 responsible for the final steps of cortisol and aldosterone synthesis, respectively, are believed to be duplicate genes with distinctive promoters. Our sequence analysis uncovers that these two genes share great homology in the proximal upstream regions, but insertion of Alu and L1 elements drives promoters divergent. Each CYP11B promoter contains two Alu elements embedded in a truncated L1 element, breaking L1 into three disconnected fragments. Alu functions as an enhancer in both genes regardless of orientation and copy number. Insertion of Alu upstream of a SV40 promoter also elevates promoter activity. However, the effect of Alu on CYP11B1 is blocked by a second L1 element (CYP11B1-L1.2) inserted between the first one and the conserved proximal upstream region. Although CYP11B1-L1.2 is 5'-truncated and lacks a functional ORF, replacing it with a fluorescent gene demonstrates that the element can be transcribed from the (CYP11B1 core promoter in an opposite direction and a smaller magnitude compared to CYP11B1. Deletion of CYP11B1-L1.2 greatly increases CYP11B1 promoter activity and restores the enhancing effect of Alu. The Ad5 and SF-1 binding elements conserved in the proximal core promoter play a role in basal expression of both genes. Mutation of the Ad5 site reduces promoter activity to the minimal level. ERR alpha is the transcription factor interacting with Ad5 during basal expression. The core promoters of both genes are also conserved in mouse and rat despite the fact that the sites corresponding to cre, Ad5, and SF-1 in rodent Cyp11b1 promoters deviate from consensus. (C) 2011 Elsevier Inc. All rights reserved.