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J. Biol. Chem., Vol. 279, Issue 32, 33398-33408, August 6, 2004

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Expression of the 7 Isoform of Hepatocyte Nuclear Factor (HNF) 4 Is Activated by HNF6/OC-2 and HNF1 and Repressed by HNF41 in the Liver^*

Nadège Briançon, Alain Bailly, Frédéric Clotman¶, Patrick Jacquemin¶||, Frédéric P. Lemaigre¶**, and Mary C. Weiss**

From the Unité de Génétique de la Différenciation, URA 2578 du CNRS, Département de Biologie du Développement, Institut Pasteur, Paris Cedex 15 75724, France and the ^¶Hormone and Metabolic Research Unit, Institute of Cellular Pathology and Université Catholique de Louvain, Avenue Hippocrate 75, Brussels B-1200, Belgium

The hepatocyte nuclear factor (HNF) 4 gene possesses two promoters, proximal P1 and distal P2, whose use results in HNF41 and HNF47 transcripts, respectively. Both isoforms are expressed in the embryonic liver, whereas HNF41 is almost exclusively in the adult liver. A 516-bp fragment, encompassing a DNase I-hypersensitive site associated with P2 activity that is still retained in adult liver, contains functional HNF1 and HNF6 binding sites and confers full promoter activity in transient transfections. We demonstrate a critical role of the Onecut factors in P2 regulation using site-directed mutagenesis and embryos doubly deficient for HNF6 and OC-2 that show reduced hepatic HNF47 transcript levels. Transient transgenesis showed that a 4-kb promoter region is sufficient to drive expression of a reporter gene in the stomach, intestine, and pancreas, but not the liver, for which additional activating sequences may be required. Quantitative PCR analysis revealed that throughout liver development HNF47 transcripts are lower than those of HNF41. HNF41 represses P2 activity in transfection assays and as deduced from an increase in P2-derived transcript levels in recombinant mice in which HNF41 has been deleted and replaced by HNF47. We conclude that although HNF6/OC-2 and perhaps HNF1 activate the P2 promoter in the embryo, increasing HNF41 expression throughout development causes a switch to essentially exclusive P1 promoter activity in the adult liver.

Received for publication, May 12, 2004

^* 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 Figs. S1-S4 and additional experimental procedures and results.

Recipient of a fellowship from the Ministère de l'Enseignement Supérieur, de la Recherche et de la Technologie and from the Association pour la Recherche contre le Cancer, France.

^|| Research associate of the Fonds National de la Recherche Scientifique, Belgium.

^** Recipients of Human Frontiers Science Program Grant GR0303/2000-M.

Supported by the Belgian State Program on Interuniversity Poles of Attraction, the Delegation Generale Higher Education and Scientific Research of the French Community of Belgium, and the Fund for Scientific Medical Research, Belgium.

Supported by a grant from the Association pour la Recherche contre le Cancer and by an agreement with Baylor College of Medicine/Institut Pasteur, which in turn was supported by National Institutes of Health Grant 1 U01 DK63588-01 (coordinator G. Darlington). To whom correspondence should be addressed: Dépt. de Biologie du Développment, Institut Pasteur, 25 rue du Dr. Roux, Paris Cedex 15 75724, France. E-mail: mweiss{at}pasteur.fr.

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