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

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 Hnf-/- 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.