Synergistic Action of Hepatocyte Nuclear Factors 3 and 6 onCYP2C12 Gene Expression and Suppression by Growth Hormone-activated STAT5b

Delesque-Touchard, Nathalie; Park, Soo-Hee; Waxman, David J.

doi:10.1074/jbc.m004027200

Cited by 67 publications

(63 citation statements)

References 50 publications

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“…5B) is transcriptional synergy, whereby HNF-6 cooperates with another LETF to stimulate the target gene promoter, as is the case for the stimulation of the Cyp2c12 gene by HNF-6 and FoxA2. 50 These first two mechanisms may be combined (Fig. 5D) as when HNF-6 and HNF-1␣ stimulate transcription of the HNF-4␣ gene synergistically.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2004

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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

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Section: Discussionmentioning

confidence: 99%

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

et al. 2004

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“…Two liver-enriched transcription factors, HNF6 and HNF3␤, display a 2-to 3-fold female bias in their expression in rat liver (20,52) and regulate the promoter of CYP2C12, a highly female-spe-cific gene (8). Furthermore, three female-specific liver transcription factors that are STAT5 dependent and GH regulated have been identified in mouse liver (23).…”

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confidence: 99%

Impact of CUX2 on the Female Mouse Liver Transcriptome: Activation of Female-Biased Genes and Repression of Male-Biased Genes

Conforto

Zhang

Sherman

et al. 2012

Molecular and Cellular Biology

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122

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The growth hormone-regulated transcription factors STAT5 and BCL6 coordinately regulate sex differences in mouse liver, primarily through effects in male liver, where male-biased genes are upregulated and many female-biased genes are actively repressed. Here we investigated whether CUX2, a highly female-specific liver transcription factor, contributes to an analogous regulatory network in female liver. Adenoviral overexpression of CUX2 in male liver induced 36% of female-biased genes and repressed 35% of male-biased genes. In female liver, CUX2 small interfering RNA (siRNA) preferentially induced genes repressed by adenovirus expressing CUX2 (adeno-CUX2) in male liver, and it preferentially repressed genes induced by adeno-CUX2 in male liver. CUX2 binding in female liver chromatin was enriched at sites of male-biased DNase hypersensitivity and at genomic regions showing male-enriched STAT5 binding. CUX2 binding was also enriched near genes repressed by adeno-CUX2 in male liver or induced by CUX2 siRNA in female liver but not at genes induced by adeno-CUX2, indicating that CUX2 binding is preferentially associated with gene repression. Nevertheless, direct CUX2 binding was seen at several highly female-specific genes that were positively regulated by CUX2, including A1bg, Cyp2b9, Cyp3a44, Tox, and Trim24. CUX2 expression and chromatin binding were high in immature male liver, where repression of adult male-biased genes and expression of adult femalebiased genes are common, suggesting that the downregulation of CUX2 in male liver at puberty contributes to the developmental changes establishing adult patterns of sex-specific gene expression. S ex differences in liver gene expression are widespread and affect a broad range of physiological processes, including steroid and drug metabolism, pheromone binding, and lipid metabolism. Hepatic sex-biased genes are regulated by growth hormone (GH) (35, 49), which is secreted by the pituitary gland in a sex-specific manner in rats, mice, and humans (16,28,44,53). Pituitary GH secretion is highly pulsatile in adult male rats and mice, where strong plasma peaks of GH are followed by periods when GH levels are below detection, whereas GH secretion is more frequent in females, resulting in a more continuous exposure to circulating GH. These sexually dimorphic plasma GH patterns stimulate sex differential patterns of tyrosine phosphorylation/activation and nuclear translocation of the transcription factors STAT5a and STAT5b (collectively, STAT5) (50). Thus, STAT5 activation is persistent in female liver but is intermittent in male liver, where it coincides with the onset of each plasma GH pulse (4, 43, 54). STAT5 positively regulates ϳ90% of male-biased genes and negatively regulates ϳ60% of female-biased genes in male mouse liver (5). STAT5 binding sites are found near 35 to 40% of sex-specific genes, suggesting they are directly regulated by STAT5 (54). However, a majority of sex-specific genes do not respond rapidly to GH-activated STAT5, suggesting indirect regulatory mechani...

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“…These findings suggest that GH can be involved in female-specific expression of the Cyp2b9 gene by modulation of FoxA2 expression. Similar GH-dependent female-dominant expression is observed in rat HNF6 and is believed to be a factor causing female-specific expression of the rat CYP2C12 gene (Delesque-Touchard et al, 2000).…”

Section: Discussionmentioning

confidence: 54%

“…FoxA2 is reported to be involved in the female-predominant expression of rat CYP2C12 mRNA (Delesque-Touchard et al, 2000); however, transcriptional activation of the CYP2C12 gene by FoxA2 is not high, and synergistic transcription was observed by combination with HNF6. Enhanced transcription by FoxA2 and HNF6 has been shown in several genes in the liver (Rausa et al, 2003).…”

Section: Discussionmentioning

confidence: 97%

Forkhead Box A2–Mediated Regulation of Female-Predominant Expression of the MouseCyp2b9Gene

Hashita

Sakuma²,

Akada³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The regulation mechanism of female-predominant expression of the mouse Cyp2b9 gene was investigated in vivo and in vitro. Luciferase reporter assay revealed that the ؊234/؊194 region of the Cyp2b9 gene may be responsible for sexually dimorphic expression. There is a predicted forkhead box A2 (FoxA2) (hepatic nuclear factor 3␤)-binding site in this region. Chromatin immunoprecipitation assay indicated that the binding protein to the site was FoxA2 in 5-week-old female mice, whereas this protein was found in both sexes at age 3 weeks, in accordance with our previous observation on the developmental expression of this gene.Mutation of the predicted FoxA2 site in the reporter construct containing the ؊234/؉18 fragment led to complete elimination of luciferase activity, but deletion of the ؊234/؊194 region resulted in considerable transcriptional activity, suggesting that by mutating the FoxA2-binding site a potent suppressor might bind to eliminate activity, whereas by deleting this region it could not. Sexually dimorphic secretion of growth hormone is involved in femalepredominant expression of the gene, and the ؊234/؊194 region was also responsible for suppressing the expression by male-type secretion.

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Synergistic Action of Hepatocyte Nuclear Factors 3 and 6 onCYP2C12 Gene Expression and Suppression by Growth Hormone-activated STAT5b

Cited by 67 publications

References 50 publications

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

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

Impact of CUX2 on the Female Mouse Liver Transcriptome: Activation of Female-Biased Genes and Repression of Male-Biased Genes

Forkhead Box A2–Mediated Regulation of Female-Predominant Expression of the MouseCyp2b9Gene

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