Transcription factor HNF-6/OC-1 inhibits the stimulation of the HNF-3alpha/Foxa1 gene by TGF-beta in mouse liver.
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.
Plumb-Rudewiez
Nicolas
N
Hormone and Metabolic Research Unit, Institute of Cellular Pathology and Université Catholique de Louvain, Brussels, Belgium.
Clotman
Frédéric
F
Strick-Marchand
Hélène
H
Pierreux
Christophe E
CE
Weiss
Mary C
MC
Rousseau
Guy G
GG
Lemaigre
Frédéric P
FP
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D051541:Hepatocyte Nuclear Factor 3-alpha; D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins / Q000378:metabolism*; D008099:Liver / Q000196:embryology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C496500:Foxa1 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C496606:Onecut1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta