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Cooperative Interaction between Hepatocyte Nuclear Factor 4 and GATA Transcription Factors Regulates ATP-Binding Cassette Sterol Transporters ABCG5 and ABCG8

Koichi Sumi,^1,, Toshiya Tanaka,^1, Aoi Uchida,¹ Kenta Magoori,¹ Yasuyo Urashima,¹ Riuko Ohashi,² Hiroto Ohguchi,¹ Masashi Okamura,¹ Hiromi Kudo,¹ Kenji Daigo,¹ Takashi Maejima,¹ Noriaki Kojima,¹ Iori Sakakibara,¹ Shuying Jiang,² Go Hasegawa,² Insook Kim,³ Timothy F. Osborne,⁴ Makoto Naito,² Frank J. Gonzalez,³ Takao Hamakubo,¹ Tatsuhiko Kodama,¹ and Juro Sakai^1*

Laboratory of Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan,¹ Department of Cellular Function, Division of Cellular and Molecular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan,² Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,³ Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92717-3900⁴

Received 6 October 2006/ Returned for modification 6 December 2006/ Accepted 26 March 2007

Cholesterol homeostasis is maintained by coordinate regulation of cholesterol synthesis and its conversion to bile acids in the liver. The excretion of cholesterol from liver and intestine is regulated by ATP-binding cassette half-transporters ABCG5 and ABCG8. The genes for these two proteins are closely linked and divergently transcribed from a common intergenic promoter region. Here, we identified a binding site for hepatocyte nuclear factor 4 (HNF4) in the ABCG5/ABCG8 intergenic promoter, through which HNF4 strongly activated the expression of a reporter gene in both directions. The HNF4-responsive element is flanked by two conserved GATA boxes that were also required for stimulation by HNF4. GATA4 and GATA6 bind to the GATA boxes, coexpression of GATA4 and HNF4 leads to a striking synergistic activation of both the ABCG5 and the ABCG8 promoters, and binding sites for HNF4 and GATA were essential for maximal synergism. We also show that HNF4, GATA4, and GATA6 colocalize in the nuclei of HepG2 cells and that a physical interaction between HNF4 and GATA4 is critical for the synergistic response. This is the first demonstration that HNF4 acts synergistically with GATA factors to activate gene expression in a bidirectional fashion.

Published ahead of print on 2 April 2007.

K.S. and T.T. contributed equally to this work.

Present address: Nippon Bio-Rad Laboratories, Tokyo 116-0014, Japan.

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