Transcription factor HNF-6/OC-1 inhibits the stimulation of the HNF-3α/Foxa1 gene by TGF-β in mouse liver
✍ Scribed by Nicolas Plumb-Rudewiez; Frédéric Clotman; Hélène Strick-Marchand; Christophe E. Pierreux; Mary C. Weiss; Guy G. Rousseau; Frédéric P. Lemaigre
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 305 KB
- Volume
- 40
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
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-3alpha/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-beta) signaling was increased both in Hnf6(-/-) liver and in Hnf6(-/-) BMEL cell lines. Using these cell lines, we demonstrated that TGF-beta signaling was increased in the absence of HNF-6, and that this resulted from upregulation of TGF-beta receptor II expression. We also found that TGF-beta can stimulate the expression of Foxa1 in Hnf6(+/+) cells and that inhibition of TGF-beta 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-beta signaling via increased expression of the TGF-beta receptor II. We further conclude that HNF-6 inhibits Foxa1 by inhibiting the activity of the TGF-beta 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.