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J. Biol. Chem., Vol. 279, Issue 4, 2955-2961, January 23, 2004

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Hepatic Erythropoietin Gene Regulation by GATA-4^*

Christof Dame¶, Martha C. Sola, Kim-Chew Lim||, Kelly M. Leach, Joachim Fandrey**, Yaluan Ma**, Gisela Knöpfle, James Douglas Engel||, and Jörg Bungert

From the Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610, the Division of Neonatology, University of Florida, Gainesville, Florida 32610, the ^||Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, the ^**Institute of Physiology, University of Essen, Essen 45147, Germany, and the Department of Pathology, University of Bonn, Bonn 53127, Germany

Erythropoietin production switches from fetal liver to adult kidney during development. GATA transcription factors 2 and 3 could be involved in modulating this switch, because they were shown to negatively regulate erythropoietin gene transcription through a promoter proximal GATA site. Herein, we analyzed the role of several GATA factors in the regulation of the erythropoietin gene in human liver and in hepatoma cells. Although GATA-3 expression in hepatocytes increases during human development, erythropoietin mRNA accumulation is unaltered in mutant mice lacking GATA-3. We found that GATA-2, -3, -4, and -6 are all expressed in human hepatocytes and that GATA-4 exhibits the most prominent Epo promoter binding activity in vitro and in vivo. Inhibition of GATA-4 expression by RNA interference leads to a dramatic reduction in Epo gene transcription in Hep3B cells. Moreover, GATA-4 expression is high and limited to hepatocytes in the fetal liver, whereas GATA-4 expression in the adult liver is low and restricted to epithelial cells surrounding the biliary ducts. Thus, GATA-4 is critical for transcription of the Epo gene in hepatocytes and may contribute to the switch in the site of Epo gene expression from the fetal liver to the adult kidney.

Received for publication, September 22, 2003 , and in revised form, October 27, 2003.

^* This work was supported by the Deutsche Forschungsgemeinschaft (DA 484/1-1 to C. D. and FA 225/18-1 to J. F.), by the Howard Hughes Medical Institute (Research Resources Program UF to J. B.), and by National Institutes of Health Grant DK52356 (to J. B.). 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.

^¶ Current address: Charité–Medical School University of Berlin, Department of Neonatology, Campus Virchow Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany.

To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Florida, P. O. Box 100245, Gainesville, FL 32610. Tel.: 352-392-0121; Fax: 352-392-2953; E-mail: jbungert{at}college.med.ufl.edu.

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