Gene expression in a young multigene family: Tissue-specific differences in the expression of the human alcohol dehydrogenase genes ADH1, ADH2, and ADH3

Celeste J. Brown, L. U. Zhang, Howard J. Edenberg

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Three human alcohol dehydrogenase genes, ADH1, ADH2, and ADH3, were formed by tandem duplications and have since diverged in their tissue-specific and developmental expression. Their proximal promoters remain 80-84% identical in sequence, approximately the same degree of identity as at synonymous sites in the coding regions of these three genes. To understand the evolution of tissue specificity, gene expression must be studied in many different cells and tissues. A systematic comparison of their promoters reveals the effects of subtle sequence differences on the binding of nuclear proteins to their cis-acting elements. There are differences in the affinity with which some proteins are bound to altered sites including C/EBP sites, USF/MLTF sites, and the G3T site (which binds Sp1). There are also differences in the sites that are occupied, e.g., CTF/NF-I-related sites. These sequence differences are reflected in differences in gene expression in three cell lines. In H4IIE-C3 hepatoma cells, the ADH1 promoter was more active than the ADH2 promoter, and the ADH3 promoter was nearly nonfunctional. In HeLa cells, both ADH1 and ADH2 promoters directed expression; again the ADH3 promoter was extremely weak. None of the three promoters had much activity in CV-1 cells. Coexpression of C/EBPα greatly stimulated expression of the ADH1 promoter in HeLa cells and in CV-1 cells, but only weakly stimulated expression in H4IIE- C3 cells. The stimulation of the ADH1 promoter by C/EBPα was comparable to that of ADH2, despite the weaker binding to the C/EBP sites that flank the TATA box in ADH1. The ADH3 promoter was not greatly stimulated by C/EBPα, despite good binding of C/EBPα. These results demonstrate that small differences in the cis-acting elements affect affinity of binding by transcription factors and the pattern of gene expression.

Original languageEnglish (US)
Pages (from-to)187-196
Number of pages10
JournalDNA and Cell Biology
Volume15
Issue number3
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

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