Transcription Factor Hnf–6/Oc–1 Inhibits the Stimulation of the Hnf–3 /Foxa1 Gene by Tgf–B 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-3␣/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-␤) signaling was increased both in Hnf6 ؊/؊ liver and in Hnf6 ؊/؊ BMEL cell lines. Using these cell lines, we demonstrated that TGF-␤ signaling was increased in the absence of HNF-6, and that this resulted from upregulation of TGF-␤ receptor II expression. We also found that TGF-␤ can stimulate the expression of A network of liver-enriched transcription factors (LETFs) controls differentiation and morphogenesis of the liver. 1-3 It comprises factors from several families that have been identified through biochemical and genetic studies. These include the CCAAT/enhancer binding proteins, the proline acidrich factors, the homeodomain proteins of the hepatocyte nuclear factor (HNF)-1 family, winged helix proteins (HNF-3/FoxA), nuclear receptors (HNF-4, LXR, FXR and FTF/hB1F/CPF families), and the Onecut (OC) factors (HNF-6/OC-1, OC-2 and OC-3). These LETFs regulate the expression of genes whose products control the development of the liver and its physiological functions. Evidence for a network of LETFs stemmed from studies based on transfection of hepatoma lines, which showed that HNF-1␣ and HNF-4 can control each other. 4 -7 Other groups extended this notion by showing that a combination of LETFs acting in synergy can directly regulate the expression of a transcription factor

Transcriptional activation by growth hormone of HNF-6-regulated hepatic genes, a potential mechanism for improved liver repair during biliary injury in mice

“…Increasing HNF-6 expression in normal liver by AdHNF-6 vectors or in BDL liver by GH administration was associated with downregulation of TGFb2R transcripts, suggesting that HNF-6 is involved in the transcriptional inhibition of TGFb2R. In support of the possibility of TGFb2R-negative transcriptional regulation by HNF-6, TGFb2R expression and TGF-␤ signaling pathways were upregulated in embryonic liver of HNF-6-null mice (6,28). Our results demonstrating parallel suppression of ␣-SMA expression, a marker for hepatic stellate cells and portal fibroblast-dependent fibrogenesis (10,29,43), thus provide a mechanistic basis for previously seen antifibrotic effects of GH administration in BDL rats (33).…”

The Transcription Factor Hepatocyte Nuclear Factor-6/Onecut-1 Controls the Expression of Its Paralog Onecut-3 in Developing Mouse Endoderm

“…Whereas independent inactivation of Hnf6 or Oc2 does not affect Hnf4 expression in liver, the combined inactivation of Hnf6 and Oc2 strongly reduces expression of the ␣7 isoform of HNF-4 (26). The expression of Hnf3␣ is also controlled by HNF-6 in the liver, but via an inhibitory, transforming growth factor ␤-dependent mechanism (27). In the pancreas, HNF-6 is required for Oc3 expression (this paper) and HNF-6 controls Hnf1␤ (24) and Ngn3 (15) expression during endocrine differentiation.…”

Tissue-specific disallowance of housekeeping genes: The other face of cell differentiation

“…Cell culture and antagomir treatment BMEL cells were cultured as previously described (Plumb-Rudewiez et al 2004), plus glutamine and hepatocyte-like differentiation was obtained by inducing the formation of floating aggregates of BMEL cells ). For miR-122 inhibition, we used antagomirs (Eurogentec).…”