title: A retroviral repetitive element confers tissue-specificity to the human alcohol dehydrogenase 1C (ADH1C) gene.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5122, USA.
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Chen
authors.forename: Kristie
authors.initials: K
authors.lastname: Carr
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Jerome
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
mesh_terms: D000426:Alcohol Dehydrogenase / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D023081:CCAAT-Binding Factor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D018983:DNA Footprinting; D003850:Deoxyribonuclease I; D015971:Gene Expression Regulation, Enzymologic; D005809:Genes, Regulator; D006367:HeLa Cells; D006801:Humans; D009928:Organ Specificity / Q000235:genetics*; D051381:Rats; D012190:Retroviridae / Q000235:genetics; D020079:Terminal Repeat Sequences / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D023081:CCAAT-Binding Factor; D014157:Transcription Factors; C402244:nuclear factor Y; D000426:Alcohol Dehydrogenase; D003850:Deoxyribonuclease I