A retroviral repetitive element confers tissue-specificity to the human alcohol dehydrogenase 1C (ADH1C) gene
A retroviral repetitive element confers tissue-specificity to the human alcohol dehydrogenase 1C (ADH1C) gene
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DOI：
10.1089/104454902320908441
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发表时间：
2002-11-01
影响因子：
3.1
通讯作者：
Edenberg, HJ
中科院分区：
文献类型：
--
作者：
Chen, HJ;Carr, K;Edenberg, HJ
人类ADH 1A、ADH 1B和ADH 1C基因编码代谢乙醇的乙醇脱氢酶（ADH）。它们由最近的串联重复进化而来，具有相似的近端顺式作用元件，但组织特异性不同。我们假设远端顺式作用元件赋予组织特异性。在这篇文章中，我们确定了多个顺式作用元件在ADH 1C上游区域。在bp-1078到-622和bp-3957到-2651的片段中的负元件分别使转录活性降低到41%和14%。在H4 IIE-C3肝癌细胞中，bp-1503和-1053之间区域的组织特异性调控元件刺激转录6倍，但在HeLa细胞中将转录降低至23%。该调控元件被定位到与人内源性逆转录病毒ERV 9的长末端重复内的U3重复相似的重复序列。两种细胞系之间表达的30倍差异表明，在创建三个I类ADH基因的复制后插入的上游U3元件在调节ADH 1C的组织特异性中起重要作用。普遍存在的核因子-Y（NF-Y）和H4 IIE-C3/肝脏特异性因子与亚重复序列结合。这一结果表明，组织特异性可能是由这两个转录因子的组合调控。
The human ADH1A, ADH1B, and ADH1C genes encode alcohol dehydrogenases (ADHs) that metabolize ethanol. They evolved by recent tandem duplications and have similar proximal cis-acting elements, but differ in tissue-specificity. We hypothesized that distal cis-acting elements confer tissue-specificity. In this article, we identify multiple cis-acting elements in the ADH1C upstream region. Negative elements in the fragments from bp -1078 to -622 and from bp -3957 to -2651 decreased transcription activity to 41 and 14%, respectively. A tissue-specific regulatory element in the region between bp -1503 and -1053 stimulated transcription sixfold in H4IIE-C3 hepatoma cells but reduced transcription to 23% in HeLa cells. This regulatory element was mapped to a repetitive sequence that is similar to the U3 repeat within the long terminal repeat of human endogenous retrovirus ERV9. The 30-fold difference in expression between two cell lines demonstrates that this upstream U3 element, which inserted after the duplications that created the three class I ADH genes, plays an important role in regulating tissue-specificity of ADH1C. The ubiquitous Nuclear factor-Y (NF-Y) and an H4IIE-C3/liver-specific factor bound to the subrepeat sequence. This result suggested that tissue specificity might result from combinatorial regulation by these two transcription factors.