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Gene Review

ONECUT1  -  one cut homeobox 1

Homo sapiens

Synonyms: HNF-6, HNF6, HNF6A, Hepatocyte nuclear factor 6, One cut domain family member 1, ...
 
 
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Disease relevance of ONECUT1

  • Human hepatoma (HepG2) cotransfection assays demonstrated that HNF-6 synergistically stimulated FoxA2 but not FoxA1 or FoxA3 transcriptional activity, and protein-binding assays showed that this protein interaction required the HNF-6 Cut-Homeodomain and FoxA2 winged-helix DNA binding domains [1].
  • We therefore tested the hypothesis that variability in the HNF-6 gene is associated with subsets of Type II (non-insulin-dependent) diabetes mellitus and estimates of insulin secretion in glucose tolerant subjects [2].
  • They also suggest that HNF-6 is a candidate gene for diabetes mellitus in humans [3].
  • The Gly/Arg972 of insulin receptor substrate-1 (IRS-1), the Thr/Ile130 of the hepatocyte nuclear factor-4alpha (HNF-4alpha), the Pro/Ala75 of HNF-6, and the Ile/Leu27, Ala/Val93, and Ser/Asn4s7 polymorphisms of the HNF-lalpha gene were examined for association with birth weight and length and the ponderal index [4].
 

High impact information on ONECUT1

  • Binding of HNF-6 to DNA is required for inhibition of glucocorticoid receptor activity [5].
  • Interestingly, the extent of nucleosome acetylation did not decrease at either regulatory region, and HNF-6 and HNF-1alpha, as well as components of the TFIID, remained associated with the proximal promoter during the repressed state [6].
  • In this context we investigate here the role of the LETF hepatocyte nuclear factor 6 (HNF-6; also called Onecut-1) during hepatocyte differentiation [7].
  • Using a combination of in vivo and in vitro gain- and loss-of-function approaches, we demonstrate that HNF-6 stimulates endogenous g6pc gene expression directly via a synergistic and interdependent action with HNF-4 and that it involves coordinate recruitment of the coactivator PGC-1alpha [7].
  • We show that HNF-6 knockout mouse fetuses have delayed expression of glucose-6-phosphatase (g6pc), which catalyzes the final step of gluconeogenesis and is a late marker of hepatocyte maturation [7].
 

Biological context of ONECUT1

  • Furthermore, we show that the HNF-6 Cut-Homeodomain sequences were sufficient to synergistically stimulate FoxA2 transcriptional activation by recruiting the p300/CBP coactivator proteins [1].
  • Furthermore, chromatin immunoprecipitation assays with hepatoma cells demonstrated that increased levels of both C/EBPalpha and HNF6 proteins were required to stimulate association of these transcription factors and the CBP coactivator protein with the endogenous mouse Foxa2 promoter region [8].
  • Stability of the hepatocyte nuclear factor 6 transcription factor requires acetylation by the CREB-binding protein coactivator [9].
  • The recognition properties of OC-2 for binding sites present in regulatory regions of liver-expressed genes differ from, but overlap with, those of HNF-6 [10].
  • Like HNF-6, OC-2 stimulates transcription of the hnf-3beta gene in transient transfection experiments, suggesting that OC-2 participates in the network of transcription factors required for liver differentiation and metabolism [10].
 

Anatomical context of ONECUT1

  • Transcription factors of the ONECUT class, whose prototype is hepatocyte nuclear factor (HNF)-6, are characterized by the presence of a single cut domain and by a peculiar homeodomain (Lannoy, V. J., Bürglin, T. R., Rousseau, G. G., and Lemaigre, F. P. (1998) J. Biol. Chem. 273, 13552-13562) [10].
  • Temporal Regulation of Enhancer Function in Intestinal Epithelium: A ROLE FOR ONECUT FACTORS [11].
  • An examination of intestinal expression patterns showed that all three OC factors are expressed at detectable levels in adult mouse duodenum, with OC-2 predominant [11].
  • During mouse development, HNF-6 is expressed in the epithelial cells that are precursors of the exocrine and endocrine pancreatic cells [3].
  • Hepatocyte nuclear factor-6 (HNF-6), a liver-enriched transcription factor, controls the development of various tissues, such as the pancreas and liver, and regulates the expression of several hepatic genes [12].
 

Associations of ONECUT1 with chemical compounds

  • We showed that acetylation of the HNF6 protein by CBP increased both HNF6 protein stability and its ability to stimulate transcription of the glucose transporter 2 promoter [9].
  • Transcription factors of the ONECUT class, whose prototype is HNF-6, contain a single cut domain and a divergent homeodomain characterized by a phenylalanine at position 48 and a methionine at position 50 [13].
  • Mutation of the HNF6 Cut domain lysine 339 residue to an arginine residue abrogated CBP acetylation, which is required for HNF6 protein stability [9].
  • Moreover, HNF-6 stimulates the enhancer in synergy with the retinoic-acid-receptor-related orphan receptor alpha (RORalpha), which binds to a neighbouring site in the s1 region [14].
 

Physical interactions of ONECUT1

  • On a target gene for which the homeodomain is required for DNA binding, but not for transcriptional stimulation, HNF-6 interacts with the coactivator p300/CBP-associated factor but not with CBP [13].
 

Regulatory relationships of ONECUT1

  • AdHNF6 infection alone caused a 2-fold increase in hepatic Glut-2 levels, suggesting that HNF 6 stimulates in vivo transcription of the Glut-2 gene [15].
 

Other interactions of ONECUT1

 

Analytical, diagnostic and therapeutic context of ONECUT1

  • Co-immunoprecipitation assays with liver protein extracts demonstrate an association between the HNF6 and C/EBPalpha transcription factors and the CBP coactivator protein in vivo [8].
  • We report the identification and characterization of simple tandem repeat DNA polymorphisms in the genes encoding HNF-3alpha, -3beta, -3gamma, -4gamma, and -6 and the mapping of HNF-6 to chromosome bands 15q21.1-21.2 by fluorescence in situ hybridization [20].
  • 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 [21].
  • In vitro footprinting analysis and electromobility shift assays identified binding of hepatic nuclear factor 6 (HNF6), signal transducer and activator of transcriptions (Stat5) and nuclear factor 1 (NF1) in liver nuclear extracts to the 160 bp proximal promoter [22].

References

  1. Association between hepatocyte nuclear factor 6 (HNF-6) and FoxA2 DNA binding domains stimulates FoxA2 transcriptional activity but inhibits HNF-6 DNA binding. Rausa, F.M., Tan, Y., Costa, R.H. Mol. Cell. Biol. (2003) [Pubmed]
  2. Hepatocyte nuclear factor-6: associations between genetic variability and type II diabetes and between genetic variability and estimates of insulin secretion. Møller, A.M., Ek, J., Durviaux, S.M., Urhammer, S.A., Clausen, J.O., Eiberg, H., Hansen, T., Rousseau, G.G., Lemaigre, F.P., Pedersen, O. Diabetologia (1999) [Pubmed]
  3. Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine gene ngn3. Jacquemin, P., Durviaux, S.M., Jensen, J., Godfraind, C., Gradwohl, G., Guillemot, F., Madsen, O.D., Carmeliet, P., Dewerchin, M., Collen, D., Rousseau, G.G., Lemaigre, F.P. Mol. Cell. Biol. (2000) [Pubmed]
  4. Variability of the insulin receptor substrate-1, hepatocyte nuclear factor-1alpha (HNF-1alpha), HNF-4alpha, and HNF-6 genes and size at birth in a population-based sample of young Danish subjects. Rasmussen, S.K., Urhammer, S.A., Hansen, T., Almind, K., Møller, A.M., Borch-Johnsen, K., Pedersen, O. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  5. Antiglucocorticoid activity of hepatocyte nuclear factor-6. Pierreux, C.E., Stafford, J., Demonte, D., Scott, D.K., Vandenhaute, J., O'Brien, R.M., Granner, D.K., Rousseau, G.G., Lemaigre, F.P. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  6. Mitogen-Activated Protein Kinase-Mediated Disruption of Enhancer-Promoter Communication Inhibits Hepatocyte Nuclear Factor 4{alpha} Expression. Hatzis, P., Kyrmizi, I., Talianidis, I. Mol. Cell. Biol. (2006) [Pubmed]
  7. Threshold levels of hepatocyte nuclear factor 6 (HNF-6) acting in synergy with HNF-4 and PGC-1alpha are required for time-specific gene expression during liver development. Beaudry, J.B., Pierreux, C.E., Hayhurst, G.P., Plumb-Rudewiez, N., Weiss, M.C., Rousseau, G.G., Lemaigre, F.P. Mol. Cell. Biol. (2006) [Pubmed]
  8. C/EBPalpha and HNF6 protein complex formation stimulates HNF6-dependent transcription by CBP coactivator recruitment in HepG2 cells. Yoshida, Y., Hughes, D.E., Rausa, F.M., Kim, I.M., Tan, Y., Darlington, G.J., Costa, R.H. Hepatology (2006) [Pubmed]
  9. Stability of the hepatocyte nuclear factor 6 transcription factor requires acetylation by the CREB-binding protein coactivator. Rausa, F.M., Hughes, D.E., Costa, R.H. J. Biol. Chem. (2004) [Pubmed]
  10. OC-2, a novel mammalian member of the ONECUT class of homeodomain transcription factors whose function in liver partially overlaps with that of hepatocyte nuclear factor-6. Jacquemin, P., Lannoy, V.J., Rousseau, G.G., Lemaigre, F.P. J. Biol. Chem. (1999) [Pubmed]
  11. Temporal Regulation of Enhancer Function in Intestinal Epithelium: A ROLE FOR ONECUT FACTORS. Maier, E.A., Dusing, M.R., Wiginton, D.A. J. Biol. Chem. (2006) [Pubmed]
  12. DNA recognition mechanism of the ONECUT homeodomain of transcription factor HNF-6. Iyaguchi, D., Yao, M., Watanabe, N., Nishihira, J., Tanaka, I. Structure (2007) [Pubmed]
  13. Transcriptional stimulation by hepatocyte nuclear factor-6. Target-specific recruitment of either CREB-binding protein (CBP) or p300/CBP-associated factor (p/CAF). Lannoy, V.J., Rodolosse, A., Pierreux, C.E., Rousseau, G.G., Lemaigre, F.P. J. Biol. Chem. (2000) [Pubmed]
  14. Hepatocyte nuclear factor-6 stimulates transcription of the alpha-fetoprotein gene and synergizes with the retinoic-acid-receptor-related orphan receptor alpha-4. Nacer-Cherif, H., Bois-Joyeux, B., Rousseau, G.G., Lemaigre, F.P., Danan, J.L. Biochem. J. (2003) [Pubmed]
  15. Maintaining HNF6 expression prevents AdHNF3beta-mediated decrease in hepatic levels of Glut-2 and glycogen. Tan, Y., Adami, G., Costa, R.H. Hepatology (2002) [Pubmed]
  16. Type I protein C deficiency caused by disruption of a hepatocyte nuclear factor (HNF)-6/HNF-1 binding site in the human protein C gene promoter. Spek, C.A., Lannoy, V.J., Lemaigre, F.P., Rousseau, G.G., Bertina, R.M., Reitsma, P.H. J. Biol. Chem. (1998) [Pubmed]
  17. The role of hepatic nuclear factor 1 alpha and PDX-1 in transcriptional regulation of the pdx-1 gene. Gerrish, K., Cissell, M.A., Stein, R. J. Biol. Chem. (2001) [Pubmed]
  18. Unique distance- and DNA-turn-dependent interactions in the human protein C gene promoter confer submaximal transcriptional activity. Spek, C.A., Bertina, R.M., Reitsma, P.H. Biochem. J. (1999) [Pubmed]
  19. Pattern of genes influenced by conditional expression of the transcription factors HNF6, HNF4alpha and HNF1beta in a pancreatic beta-cell line. Thomas, H., Senkel, S., Erdmann, S., Arndt, T., Turan, G., Klein-Hitpass, L., Ryffel, G.U. Nucleic Acids Res. (2004) [Pubmed]
  20. Pancreatic islet expression studies and polymorphic DNA markers in the genes encoding hepatocyte nuclear factor-3alpha, -3beta, -3gamma, -4gamma, and -6. Vaisse, C., Kim, J., Espinosa, R., Le Beau, M.M., Stoffel, M. Diabetes (1997) [Pubmed]
  21. The transcriptional activator hepatocyte nuclear factor 6 regulates liver gene expression. Samadani, U., Costa, R.H. Mol. Cell. Biol. (1996) [Pubmed]
  22. In vivo transfection of rat liver discloses binding sites conveying GH-dependent and female-specific gene expression. Gardmo, C., Mode, A. J. Mol. Endocrinol. (2006) [Pubmed]
 
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