The Onecut transcription factors HNF-6/OC-1 and OC-2 regulate early liver expansion by controlling hepatoblast migration

Margagliotti, Sabrina; Clotman, Frédéric; Pierreux, Christophe E.; Beaudry, Jean–Bernard; Jacquemin, Patrick; Rousseau, Guy; Lemaigre, Frédéric P.

doi:10.1016/j.ydbio.2007.09.013

Cited by 112 publications

(90 citation statements)

References 47 publications

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“…in mouse embryos, a deficiency in PROX1 or HNF6 in hepatoblasts does not disturb the emergence of Alb + cells from the endoderm [6,7]. Therefore, these results suggest that two populations can be distinguished during hepatic differentiation from hESCs based on the expression of PROX1 and HNF6.…”

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confidence: 71%

Promotion of the efficient metabolic maturation of human pluripotent stem cell-derived hepatocytes by correcting specification defects

et al. 2012

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Promoting the functional maturation of the desired cell types derived from human pluripotent stem cells (hPSCs) remains a major challenge, especially for hepatocytes, as routine access to metabolically functional hepatocytes would enable their use in drug toxicity screening. Although previous attempts to induce hepatic specification from hPSCs yielded cells possessing some hepatic features [1][2][3], most of these cells showed poor metabolic activities, and the responsible mechanisms are unknown. In this study, we explored the intrinsic defects in hPSCderived immature hepatocytes and tested whether correcting these defects would promote the metabolic maturation of the differentiated cells.One possible explanation for the inability to derive mature hepatic cells is incomplete specification of the differentiated cells [4] caused by the lack of some key transcription factors. To test this hypothesis, immunofluorescence staining was carried out to assess the coexpression of a panel of crucial transcription factors, including FOXA2, GATA4, HNF4A, GATA6, PROX1, HNF6 and TBX3, along with the mature hepatocyte markers ALB and CYP3A4 in hepatocyte-like cells differentiated from human embryonic stem cells (hESCs), according to a previously published protocol [5]. Although ALB was efficiently expressed and co-localized with HNF4A in hepatocyte-like cells differentiated from hESCs, CYP3A4 was rarely observed in the differentiated cultures (Supplementary information, Data S1 and Figure S1A-S1B). Surprisingly, the limited expression of CYP3A4 correlated well with the expression of PROX1 and HNF6, which also were rarely observed in the cultures. When cells at the hepatoblast stage were characterized, similar defects were already present (Supplementary information, Figure S1C-S1E). Although FOXA2, GATA4, HNF4A and GATA6 were expressed ubiquitously (> 95%) in hESC-derived AFP-positive cells, PROX1 and HNF6 were barely detectable (< 0.1%). Interestingly,

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confidence: 71%

Promotion of the efficient metabolic maturation of human pluripotent stem cell-derived hepatocytes by correcting specification defects

et al. 2012

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“…We should also consider the effects of other target genes of OC2 that were not determined in the present study. The studies using OC2-deficient mouse revealed the important roles of this transcription factor in liver and pancreas development, [25][26][27] suggesting its broad range of contribution to cellular development.…”

Section: Resultsmentioning

confidence: 99%

Onecut transcription factor OC2 is a direct target of T-bet in type-1 T-helper cells

et al. 2008

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T-box transcription factor, T-bet, has a central role in the differentiation of T-helper (Th) progenitor cells to Th1 or Th2 effector cells, partly by regulating the expression of genes such as interferon-g (IFN-g). However, the direct target genes, especially those mediating the transcriptional network initiated by T-bet, are not yet fully understood. By combining chromatin immunoprecipitation from Th1 cells with human cytosine-phosphate-guanine-island array analysis, Onecut 2 (OC2), which encodes a member of the ONECUT class of transcriptional activators, was identified as a direct target gene of T-bet. OC2 is expressed in Th1 but not Th2 cells and reporter assays showed that T-bet transactivates OC2 transcription through putative T-bet half-sites locating À451 to À347 of OC2 promoter region. Moreover, we found that OC2 binds and transactivates human T-bet promoter. These results suggest that not only cell-extrinsic regulation via the IFN-g/STAT1 pathway, but also cell-intrinsic transcriptional positive feedback loop between T-bet and OC2 could be involved in Th1 development.

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“…The transcription factors whose expression is CUX2 regulated include 11 homeobox and homeodomain-containing proteins (Cphx, CUX1, CUX2, Hmbox1, Onecut1/HNF6, Onecut2, PBX1, Prox1, Six1, Tgif2, and Zfhx4), which regulate development, differentiation, and other cellular processes (2,45). Four of these factors (CUX1, Onecut1/HNF6, Onecut2, and Prox1) are involved in liver development (15,18,31), and binding sites for one of the factors (PBX1) are enriched at male-biased liver DNase-hypersensitive sites (25). PBX1 can serve as a cofactor of other homeodomain proteins (22,38), while Tgif2 interacts with histone deacetylase I to repress gene expression (32).…”

Section: Discussionmentioning

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

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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The Onecut transcription factors HNF-6/OC-1 and OC-2 regulate early liver expansion by controlling hepatoblast migration

Cited by 112 publications

References 47 publications

Promotion of the efficient metabolic maturation of human pluripotent stem cell-derived hepatocytes by correcting specification defects

Promotion of the efficient metabolic maturation of human pluripotent stem cell-derived hepatocytes by correcting specification defects

Onecut transcription factor OC2 is a direct target of T-bet in type-1 T-helper cells

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

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