Abstract
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 -1,078 to -622 and from bp -3,957 to -2,651 decreased transcription activity to 41 and 14%, respectively. A tissue-specific regulatory element in the region between bp -1,503 and -1,053 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.
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