Transcription factor HNF-6/OC-1 inhibits the stimulation of the HNF-3α/Foxa1 gene by TGF-β in mouse liver

Authors

  • Nicolas Plumb-Rudewiez,

    1. Hormone and Metabolic Research Unit, Institute of Cellular Pathology and Université Catholique de Louvain, Brussels, Belgium
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    • N.P.-R. and F.C. contributed equally to this work.

  • Frédéric Clotman,

    1. Hormone and Metabolic Research Unit, Institute of Cellular Pathology and Université Catholique de Louvain, Brussels, Belgium
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    • N.P.-R. and F.C. contributed equally to this work.

  • Hélène Strick-Marchand,

    1. Unité de Génétique de la Différenciation, Institut Pasteur, Paris, France
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  • Christophe E. Pierreux,

    1. Hormone and Metabolic Research Unit, Institute of Cellular Pathology and Université Catholique de Louvain, Brussels, Belgium
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    • C.E.P. was senior research assistant of the FNRS (Belgium)

  • Mary C. Weiss,

    1. Unité de Génétique de la Différenciation, Institut Pasteur, Paris, France
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  • Guy G. Rousseau,

    1. Hormone and Metabolic Research Unit, Institute of Cellular Pathology and Université Catholique de Louvain, Brussels, Belgium
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  • Frédéric P. Lemaigre

    Corresponding author
    1. Hormone and Metabolic Research Unit, Institute of Cellular Pathology and Université Catholique de Louvain, Brussels, Belgium
    • Hormone and Metabolic Research Unit, Université catholique de Louvain and Institute of Cellular Pathology, Avenue Hippocrate 75, Box 7529, 1200 Brussels, Belgium
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    • fax: (32) 2-764-7507


Abstract

A network of liver-enriched transcription factors controls differentiation and morphogenesis of the liver. These factors interact via direct, feedback, and autoregulatory loops. Previous work has suggested that hepatocyte nuclear factor (HNF)-6/OC-1 and HNF-3α/FoxA1 participate coordinately in this hepatic network. We investigated how HNF-6 controls the expression of Foxa1. We observed that Foxa1 expression was upregulated in the liver of Hnf6−/− mouse embryos and in bipotential mouse embryonic liver (BMEL) cell lines derived from embryonic Hnf6−/− liver, suggesting that HNF-6 inhibits the expression of Foxa1. Because no evidence for a direct repression of Foxa1 by HNF-6 was found, we postulated the existence of an indirect mechanism. We found that the expression of a mediator and targets of the transforming growth factor beta (TGF-β) signaling was increased both in Hnf6−/− liver and in Hnf6−/− BMEL cell lines. Using these cell lines, we demonstrated that TGF-β signaling was increased in the absence of HNF-6, and that this resulted from upregulation of TGF-β receptor II expression. We also found that TGF-β can stimulate the expression of Foxa1 in Hnf6+/+ cells and that inhibition of TGF-β signaling in Hnf6−/− cells down-regulates the expression of Foxa1. In conclusion, we propose that Foxa1 upregulation in the absence of HNF-6 results from increased TGF-β signaling via increased expression of the TGF-β receptor II. We further conclude that HNF-6 inhibits Foxa1 by inhibiting the activity of the TGF-β signaling pathway. This identifies a new mechanism of interaction between liver-enriched transcription factors whereby one factor indirectly controls another by modulating the activity of a signaling pathway. (HEPATOLOGY 2004;40:1266–1274.)

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