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J. Biol. Chem., Vol. 281, Issue 29, 19809-19821, July 21, 2006

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Distant HNF1 Site as a Master Control for the Human Class I Alcohol Dehydrogenase Gene Expression^*

Jih-Shyun Su¹, Ting-Fen Tsai¹, Hua-Mei Chang^¶, Kun-Mao Chao^||, Tsung-Sheng Su^**, and Shih-Feng Tsai²

From the Faculty of Life Sciences and Institute of Genetics, National Yang-Ming University, Taipei 112, Division of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 350, ^¶Vita Genomics, Inc., Taipei County 248, ^||Department of Computer Science and Information Engineering, National Taiwan University, Taipei 106, and the ^**Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan

Gene duplication and divergence have contributed to the biochemical diversity of the alcohol dehydrogenase (ADH) family. Class I ADH is the major enzyme that catalyzes alcohol to acetaldehyde in the liver. To investigate the mechanism(s) controlling tissue-specific and temporal regulation of the three human class I ADH genes (ADH1A, ADH1B, and ADH1C), we compared genomic sequences for the human and mouse ADH loci and analyzed human ADH gene expression in BAC transgenic mice carrying different lengths of the upstream sequences of the class I ADH. A conserved noncoding sequence, located between the class I and class IV ADH (ADH7) genes, was found to be essential for directing class I ADH gene expression in fetal and adult livers. Within this region, a 275-bp fragment displaying liver-specific DNase I hypersensitivity was bound by HNF1. The HNF1-containing upstream sequence enhanced all three class I ADH promoters in an orientation-dependent manner, and the transcriptional activation depended on binding to the HNF1 site. Deletion of the conserved HNF1 site in the BAC led to the shutdown of human class I ADH gene expression in the transgenic livers, leaving ADH1C gene expression in the stomach unchanged. Moreover, interaction between the upstream element and the class I ADH gene promoters was demonstrated by chromosome conformation capture, suggesting a DNA looping mechanism is involved in gene activation. Taken together, our data indicate that HNF1 binding, at 51 kb upstream, plays a master role in controlling human class I ADH gene expression and may govern alcohol metabolism in the liver.

Received for publication, April 14, 2006

^* This work was supported by National Science Council Grant 93-3112-B-400-006- (to S. F. T.) and National Research Program for Genomic Medicine Grant 92GM064 and National Science Council Grant 93-2752-B-010-004-PAE (to T. F. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental table and figure.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Division of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 350, Taiwan. Tel.: 886-2-28267043; Fax: 886-2-28200552; E-mail: petsai{at}nhri.org.tw.

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