Evolutionary silencing of the human elastase I gene (ELA 1)
Evolutionary silencing of the human elastase I gene (ELA 1)
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DOI：
10.1093/hmg/6.6.897
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发表时间：
1997-06-01
影响因子：
3.5
通讯作者：
MacDonald, RJ
中科院分区：
文献类型：
--
作者：
Rose, SD;MacDonald, RJ
人胰腺弹性蛋白酶I基因是转录沉默的，尽管结构基因的表观完整性，转录调节序列的必要性和足够的活性大鼠同源物的转录定位在205个碱基对（bp）的转录起始，并包括一个胰腺特异性转录增强子的134 bp的71 bp的非特异性启动子的上游。人类基因在这一区域内有58个核苷酸差异，其中13个在三个功能元件中（A、B和C），通过对胰腺腺泡肿瘤细胞系的细胞转染分析，我们表明人5'侧翼基因序列中的核苷酸差异使增强子和启动子都失活，单是人类增强子三要素的变化就足以使增强子消失;相反地，将这些增强子恢复到大鼠构型部分地恢复了人增强子的活性，A元件中的两个突变和B元件中的四个突变消除了先前显示介导这些元件活性的转录因子的结合。用人启动子替换有活性的71 bp大鼠启动子也阻止表达。因此，人类弹性蛋白酶I基因的进化沉默似乎是由于突变，关键的增强子和启动子元件。
The human pancreatic elastase I gene is transcriptionally silent, despite the apparent integrity of the structural gene, The transcriptional regulatory sequences necessary and sufficient for transcription of the active rat homologue are localized within 205 base pairs (bp) of the transcriptional start and comprise a pancreas-specific transcriptional enhancer of 134 bp immediately upstream of a 71 bp non-specific promoter. The human gene has 58 nucleotide differences within this region, 13 of which are in the three functional elements (A, B and C) that constitute the enhancer, Through cell transfection analyses with a pancreatic acinar tumor cell line, we show that the nucleotide differences in the human 5' flanking gene sequences have inactivated both the enhancer and the promoter, The changes in the three elements of the human enhancer alone are sufficient to inactivate the enhancer; conversely, restores these to the rat configuration partially restores the activity of the human enhancer, The two mutations in the A element and the four mutations in the B element abolish the binding of the transcription factors previously shown to mediate the activity of these elements. Replacing the active 71 bp rat promoter with the human promoter also prevents expression. Therefore, the evolutionary silencing of the human elastase I gene appears due to mutations that inactivate crucial enhancer and promoter elements.