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Molecular and Cellular Biology, November 2001, p. 7320-7330, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7320-7330.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Regulatory Mechanisms Controlling Human Hepatocyte Nuclear Factor 4alpha Gene Expression

Pantelis Hatzis and Iannis Talianidis*

Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, 711 10 Herakleion, Crete, Greece

Received 21 March 2001/Returned for modification 2 May 2001/Accepted 3 August 2001

Hepatocyte nuclear factor 4alpha (HNF-4alpha ) (nuclear receptor 2A1) is an essential regulator of hepatocyte differentiation and function. Genetic and molecular evidence suggests that the tissue-restricted expression of HNF-4alpha is regulated mainly at the transcriptional level. As a step toward understanding the molecular mechanism involved in the transcriptional regulation of the human HNF-4alpha gene, we cloned and analyzed a 12.1-kb fragment of its upstream region. Major DNase I-hypersensitive sites were found at the proximal promoter, the first intron, and the more-upstream region comprising kb -6.5, -8.0, and -8.8. By the use of reporter constructs, we found that the proximal-promoter region was sufficient to drive high levels of hepatocyte-specific transcription in transient-transfection assays. DNase I footprint analysis and electrophoretic mobility shift experiments revealed binding sites for HNF-1alpha and -beta , Sp-1, GATA-6, and HNF-6. High levels of HNF-4alpha promoter activity were dependent on the synergism between either HNF-1alpha and HNF-6 or HNF-1beta and GATA-6, which implies that at least two alternative mechanisms may activate HNF-4alpha gene transcription. Chromatin immunoprecipitation experiments with human hepatoma cells showed stable association of HNF-1alpha , HNF-6, Sp-1, and COUP-TFII with the promoter. The last factor acts as a repressor via binding to a newly identified direct repeat 1 (DR-1) sequence of the human promoter, which is absent in the mouse homologue. We present evidence that this sequence is a bona fide retinoic acid response element and that HNF-4alpha expression is upregulated in vivo upon retinoic acid signaling.

* Corresponding author. Mailing address: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, P.O. Box 1527, 711 10 Herakleion, Crete, Greece. Phone: 30-81-391163. Fax: 30-81-391101.E-mail: talianid{at}imbb.forth.gr.

Molecular and Cellular Biology, November 2001, p. 7320-7330, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7320-7330.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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