Disease relevance of Onecut1

• In situ hybridization studies of staged specific embryos demonstrate that HNF-6 and its potential target gene, HNF-3 beta, are coexpressed in the pancreatic and hepatic diverticulum [1].
• We found that maintaining hepatic HNF-6 levels with AdH6 infection resulted in significant decreases in BEC proliferation at 15 and 24 hours after biliary obstruction compared with adenovirus control [2].
• We show in this study that inactivation of the gene coding for hepatocyte nuclear factor-6 (HNF-6) in mice led to B lymphopenia in the bone marrow and spleen [3].
• RESULTS: Elevated expression of HNF6 during mouse liver regeneration causes a significant increase in the number of hepatocytes entering DNA replication (S phase), and mouse hepatoma Hepa1-6 cells diminished for HNF6 levels by small interfering RNA transfection exhibit a 50% reduction in S phase following serum stimulation [4].

High impact information on Onecut1

• Control of liver cell fate decision by a gradient of TGF beta signaling modulated by Onecut transcription factors [5].
• METHODS: Using immunostaining, we have determined the expression pattern of HNF-6 in pancreatic ducts during mouse development [6].
• RESULTS: We show that HNF-6 is expressed in the pancreatic duct epithelium throughout development and that, in the absence of HNF-6, duct morphogenesis is perturbed [6].
• HNF-6 controls a network of genes involved in cilium formation and in hereditary polycystic diseases [6].
• CONCLUSIONS: These mouse liver regeneration studies show that increased HNF6 levels stimulate hepatocyte proliferation through transcriptional induction of cell cycle regulatory genes [4].

Chemical compound and disease context of Onecut1

• METHODS: Tail vein injection of adenovirus expressing the HNF6 complementary DNA was used to increase hepatic HNF6 levels during mouse liver regeneration induced by partial hepatectomy, and DNA replication was determined by bromodeoxyuridine incorporation [4].

Biological context of Onecut1

• Based on transfection, chromatin immunoprecipitation, and whole embryo electroporation experiments, we demonstrate that HNF-6 can bind to and stimulate the expression of the Oc3 gene [7].
• HNF6 expression in the embryonic endoderm was found to depend on an intronic enhancer [8].
• This study identifies a regulatory cascade between two paralogous transcription factors, sheds new light on the interpretation of the Hnf6 knock-out phenotype, and broadens the transcription factors network operating during development of the endoderm, liver, and pancreas [7].
• Hepatocyte nuclear factor-6 (HNF6) is a key player in this network, because it controls the initiation of the expression of pancreatic and duodenal homeobox 1 (Pdx1), the earliest marker of pancreatic precursor cells [8].
• We delineated Hnf6 regulatory regions that confer expression of a reporter gene in the embryonic endoderm but not in extraembryonic visceral endoderm [8].

Anatomical context of Onecut1

• In the present work, we examine the expression profile of the three Onecut factors in the developing mouse endoderm [7].
• HNF-6 binding activity was also found in the intestinal epithelial cell line HT29, and potential HNF-6 binding sites were present in intestinal sucrase isomaltase, cdx-2 homeodomain protein, and intestinal fatty acid binding protein promoter regions [9].
• 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 [10].
• We also found that HNF-6 is also abundantly expressed in the dorsal root ganglia, the marginal layer, and the midbrain [1].
• In the absence of Onecut factors, the shape of the activin/TGFbeta gradient is perturbed and the hepatoblasts differentiate into hybrid cells that display characteristics of both hepatocytes and biliary cells [5].

Associations of Onecut1 with chemical compounds

• In conclusion, the HNF-6 protein is a component of the complex network of hepatic transcription factors that regulates the expression of hepatic genes essential for bile acid homeostasis and cholesterol/lipid metabolism in normal and pathological conditions [11].
• HNF-6 binds to DNA as a monomer utilizing a single cut domain and a divergent homeodomain motif located at its C terminus [12].
• These results suggest that downregulation of Hnf6 expression in beta-cells during development is essential to achieve a mature, glucose-responsive beta-cell [13].

Physical interactions of Onecut1

• RESULTS: HNF-6 bound to the hepatic promoter of the glucokinase gene and stimulated its activity [14].
• OC-3 has a DNA-binding specificity similar to that of HNF-6 and it is a stimulator of gene transcription [15].
• Again, we found no evidence that HNF6 binding to its targets in chromatin is reduced in the presence of Foxa2 [16].

Enzymatic interactions of Onecut1

• Hepatocyte nuclear factor 6 (HNF-6) belongs to the family of One Cut transcription factors (also known as OC-1) and is essential for the development of the mouse pancreas, gall bladder, and the interhepatic bile ducts [12].

Regulatory relationships of Onecut1

• We hypothesized that HNF-6 controls the activity of the hepatic glucokinase promoter [14].
• We investigated how HNF-6 controls the expression of Foxa1 [10].
• The cut-homeodomain transcriptional activator HNF-6 is coexpressed with its target gene HNF-3 beta in the developing murine liver and pancreas [1].
• Moreover, HNF-6 could directly stimulate the Pdx1 promoter [17].
• We showed previously that the Onecut transcription factor HNF-6 promotes differentiation of the endocrine cell precursors in which it stimulates expression of the proendocrine gene Ngn-3 [17].

Other interactions of Onecut1

• We show that HNF-6, OC-2, and OC-3 are expressed sequentially, which defines new steps in endoderm differentiation [7].
• Inactivation of the hnf6 gene did not modify the pattern of deoxyribonuclease I hypersensitive sites but was associated with a decrease of liver glucokinase mRNA to half the control value [14].
• A vHNF1/TCF2-HNF6 cascade regulates the transcription factor network that controls generation of pancreatic precursor cells [8].
• A 516-bp fragment, encompassing a DNase I-hypersensitive site associated with P2 activity that is still retained in adult liver, contains functional HNF1 and HNF6 binding sites and confers full promoter activity in transient transfections [18].
• Because no evidence for a direct repression of Foxa1 by HNF-6 was found, we postulated the existence of an indirect mechanism [10].

Analytical, diagnostic and therapeutic context of Onecut1

• To further characterize this network, we have investigated how the expression of HNF6 is controlled in mouse endoderm, by using in vitro and in vivo protein-DNA interaction techniques combined with endoderm electroporation, transgenesis, and gene inactivation in embryos [8].
• Site-directed mutagenesis of the HNF-6 sites in the HNF-3(beta) and transthyretin promoters diminishes reporter gene expression, suggesting that HNF-6 activates transcription of these promoters [9].
• We also examined the mRNA levels of HNF6 targets in the liver using a cDNA array and found that their expression was similar in Foxa2-deficient and control mice [16].
• Chromatin immunoprecipitation using anti-HNF6 antibodies was performed on chromatin isolated from Foxa2(loxP/loxP) Alfp.Cre and control mouse livers, and HNF6 binding to its target, Glut2, was determined by quantitative PCR [16].
• Following bile duct ligation, we demonstrated that diminished HNF-6 mRNA levels correlate with a reduction in CYP7A1 mRNA expression [11].

References