hepatocyte nuclear factor 6


Summary: A onecut transcription factor that regulates expression of GENES involved in EMBRYONIC DEVELOPMENT of the PANCREAS and LIVER.

Top Publications

  1. Clotman F, Jacquemin P, Plumb Rudewiez N, Pierreux C, Van Der Smissen P, Dietz H, et al. Control of liver cell fate decision by a gradient of TGF beta signaling modulated by Onecut transcription factors. Genes Dev. 2005;19:1849-54 pubmed
    ..Thus, a gradient of activin/TGFbeta signaling modulated by Onecut factors is required to segregate the hepatocytic and the biliary lineages. ..
  2. Francius C, Clotman F. Dynamic expression of the Onecut transcription factors HNF-6, OC-2 and OC-3 during spinal motor neuron development. Neuroscience. 2010;165:116-29 pubmed publisher
    The Onecut (OC) transcription factors, namely Hepatocyte nuclear factor 6 (HNF-6), OC-2 and OC-3, are transcriptional activators expressed in liver, pancreas and nervous system during development...
  3. Rausa F, Tan Y, Costa R. Association between hepatocyte nuclear factor 6 (HNF-6) and FoxA2 DNA binding domains stimulates FoxA2 transcriptional activity but inhibits HNF-6 DNA binding. Mol Cell Biol. 2003;23:437-49 pubmed
    ..This is the first reported example of a liver-enriched transcription factor (HNF-6) functioning as a coactivator protein to potentiate the transcriptional activity of another liver factor, FoxA2. ..
  4. Margagliotti S, Clotman F, Pierreux C, Beaudry J, Jacquemin P, Rousseau G, et al. The Onecut transcription factors HNF-6/OC-1 and OC-2 regulate early liver expansion by controlling hepatoblast migration. Dev Biol. 2007;311:579-89 pubmed
    ..This network operating at the onset of liver development contains candidate genes for investigation of liver carcinogenesis. ..
  5. Espana A, Clotman F. Onecut factors control development of the Locus Coeruleus and of the mesencephalic trigeminal nucleus. Mol Cell Neurosci. 2012;50:93-102 pubmed publisher
    ..Hence, we propose that OC factors are required at early developmental stages for differentiation of the MTN neurons that are in turn necessary for maintenance of the LC. ..
  6. Tan Y, Yoshida Y, Hughes D, Costa R. Increased expression of hepatocyte nuclear factor 6 stimulates hepatocyte proliferation during mouse liver regeneration. Gastroenterology. 2006;130:1283-300 pubmed
    The hepatocyte nuclear factor 6 (HNF6 or ONECUT-1) protein is a cell-type specific transcription factor that regulates expression of hepatocyte-specific genes...
  7. Lahuna O, Fernandez L, Karlsson H, Maiter D, Lemaigre F, Rousseau G, et al. Expression of hepatocyte nuclear factor 6 in rat liver is sex-dependent and regulated by growth hormone. Proc Natl Acad Sci U S A. 1997;94:12309-13 pubmed
    ..This work provides an example of a homeodomain-containing transcription factor that is GH-regulated and also reports on the hormonal regulation of HNF-6. ..
  8. Rubins N, Friedman J, Le P, Zhang L, Brestelli J, Kaestner K. Transcriptional networks in the liver: hepatocyte nuclear factor 6 function is largely independent of Foxa2. Mol Cell Biol. 2005;25:7069-77 pubmed
    ..Overall, our studies demonstrate that HNF6 binds to and regulates its target promoters in vivo in the presence and absence of Foxa2. ..
  9. Tweedie E, Artner I, Crawford L, Poffenberger G, Thorens B, Stein R, et al. Maintenance of hepatic nuclear factor 6 in postnatal islets impairs terminal differentiation and function of beta-cells. Diabetes. 2006;55:3264-70 pubmed
    ..These results suggest that downregulation of Hnf6 expression in beta-cells during development is essential to achieve a mature, glucose-responsive beta-cell. ..

More Information


  1. Rausa F, Samadani U, Ye H, Lim L, Fletcher C, Jenkins N, et al. The cut-homeodomain transcriptional activator HNF-6 is coexpressed with its target gene HNF-3 beta in the developing murine liver and pancreas. Dev Biol. 1997;192:228-46 pubmed
    ..We discuss these expression patterns with respect to specification of hepatocytes and differentiation of the endocrine and exocrine pancreas. ..
  2. Clotman F, Lannoy V, Reber M, Cereghini S, Cassiman D, Jacquemin P, et al. The onecut transcription factor HNF6 is required for normal development of the biliary tract. Development. 2002;129:1819-28 pubmed
    ..We conclude that HNF6 is essential for differentiation and morphogenesis of the biliary tract and that intrahepatic bile duct development is controlled by a HNF6-->HNF1beta cascade...
  3. Vanhorenbeeck V, Jenny M, Cornut J, Gradwohl G, Lemaigre F, Rousseau G, et al. Role of the Onecut transcription factors in pancreas morphogenesis and in pancreatic and enteric endocrine differentiation. Dev Biol. 2007;305:685-94 pubmed
    ..In conclusion, our data reveal partially redundant roles for HNF-6 and OC-2 in developing pancreas and identify new markers for antero-posterior patterning of the gut and for enteroendocrine differentiation. ..
  4. Wang K, Holterman A. Pathophysiologic role of hepatocyte nuclear factor 6. Cell Signal. 2012;24:9-16 pubmed publisher
    b>Hepatocyte nuclear factor 6 (HNF6) is one of liver-enriched transcription factors...
  5. Lehner F, Kulik U, Klempnauer J, Borlak J. Mapping of liver-enriched transcription factors in the human intestine. World J Gastroenterol. 2010;16:3919-27 pubmed
    To investigate the gene expression pattern of hepatocyte nuclear factor 6 (HNF6) and other liver-enriched transcription factors in various segments of the human intestine to better understand the differentiation of the gut epithelium...
  6. Plumb Rudewiez N, Clotman F, Strick Marchand H, Pierreux C, Weiss M, Rousseau G, et al. Transcription factor HNF-6/OC-1 inhibits the stimulation of the HNF-3alpha/Foxa1 gene by TGF-beta in mouse liver. Hepatology. 2004;40:1266-74 pubmed
    ..This identifies a new mechanism of interaction between liver-enriched transcription factors whereby one factor indirectly controls another by modulating the activity of a signaling pathway. ..
  7. Poll A, Pierreux C, Lokmane L, Haumaitre C, Achouri Y, Jacquemin P, et al. A vHNF1/TCF2-HNF6 cascade regulates the transcription factor network that controls generation of pancreatic precursor cells. Diabetes. 2006;55:61-9 pubmed
    ..This cascade may be used to benchmark in vitro differentiation of pancreatic precursor cells from embryonic stem cells, for cell therapy of diabetes. ..
  8. Jiang X, Zhang W, Kayed H, Zheng P, Giese N, Friess H, et al. Loss of ONECUT1 expression in human pancreatic cancer cells. Oncol Rep. 2008;19:157-63 pubmed
    ..In conclusion, ONECUT1 expression is lost in pancreatic cancer cells, suggesting a tumor suppressor function in this malignancy. ..
  9. Lehner F, Kulik U, Klempnauer J, Borlak J. The hepatocyte nuclear factor 6 (HNF6) and FOXA2 are key regulators in colorectal liver metastases. FASEB J. 2007;21:1445-62 pubmed
    ..HNF6 DNA binding is selectively abrogated through lack of post-translational modification and interaction with FOXA2. Targeting of FOXA2 and HNF6 may therefore enable mechanism-based therapy for colorectal liver metastases. ..
  10. Yoshida Y, Hughes D, Rausa F, Kim I, Tan Y, Darlington G, et al. C/EBPalpha and HNF6 protein complex formation stimulates HNF6-dependent transcription by CBP coactivator recruitment in HepG2 cells. Hepatology. 2006;43:276-86 pubmed
    We previously demonstrated that formation of complexes between the DNA-binding domains of hepatocyte nuclear factor 6 (HNF6) and forkhead box a2 (Foxa2) proteins stimulated Foxa2 transcriptional activity...
  11. Gannon M, Ray M, Van Zee K, Rausa F, Costa R, Wright C. Persistent expression of HNF6 in islet endocrine cells causes disrupted islet architecture and loss of beta cell function. Development. 2000;127:2883-95 pubmed
    We used transgenesis to explore the requirement for downregulation of hepatocyte nuclear factor 6 (HNF6) expression in the assembly, differentiation, and function of pancreatic islets...
  12. Jacquemin P, Lannoy V, Rousseau G, Lemaigre F. 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. J Biol Chem. 1999;274:2665-71 pubmed
    ..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. ..
  13. Pierreux C, Poll A, Kemp C, Clotman F, Maestro M, Cordi S, et al. The transcription factor hepatocyte nuclear factor-6 controls the development of pancreatic ducts in the mouse. Gastroenterology. 2006;130:532-41 pubmed
    ..HNF-6 controls a network of genes involved in cilium formation and in hereditary polycystic diseases. Finally, HNF-6 deficiency represents a genetically defined model of pancreatic cystic disease. ..
  14. Beaudry J, Pierreux C, Hayhurst G, Plumb Rudewiez N, Weiss M, Rousseau G, et al. 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. Mol Cell Biol. 2006;26:6037-46 pubmed
    ..In this context we investigate here the role of the LETF hepatocyte nuclear factor 6 (HNF-6; also called Onecut-1) during hepatocyte differentiation...
  15. Zhang H, Ables E, Pope C, Washington M, Hipkens S, Means A, et al. Multiple, temporal-specific roles for HNF6 in pancreatic endocrine and ductal differentiation. Mech Dev. 2009;126:958-73 pubmed publisher
    ..These data confirm that HNF6 has both early and late functions in the developing pancreas and is essential for maintenance of Ngn3 expression and proper pancreatic duct morphology. ..
  16. Thomas H, Senkel S, Erdmann S, Arndt T, Turan G, Klein Hitpass L, et al. Pattern of genes influenced by conditional expression of the transcription factors HNF6, HNF4alpha and HNF1beta in a pancreatic beta-cell line. Nucleic Acids Res. 2004;32:e150 pubmed
    ..We show that the expression of the mutant P328L329del and A263insGG affects only very few transcripts and these are predominantly distinct from those induced by wild-type HNF1beta. ..
  17. Pierreux C, Vanhorenbeeck V, Jacquemin P, Lemaigre F, Rousseau G. The transcription factor hepatocyte nuclear factor-6/Onecut-1 controls the expression of its paralog Onecut-3 in developing mouse endoderm. J Biol Chem. 2004;279:51298-304 pubmed
  18. Wilding Crawford L, Tweedie Ables E, Oh Y, Boone B, Levy S, Gannon M. Gene expression profiling of a mouse model of pancreatic islet dysmorphogenesis. PLoS ONE. 2008;3:e1611 pubmed publisher
    ..This study provides a unique dataset that can act as a starting point for other investigators to explore the role of the identified genes in pancreatogenesis, islet morphogenesis and mature beta cell function. ..
  19. Stam F, Hendricks T, Zhang J, Geiman E, Francius C, Labosky P, et al. Renshaw cell interneuron specialization is controlled by a temporally restricted transcription factor program. Development. 2012;139:179-90 pubmed publisher
  20. Prevot P, Simion A, Grimont A, Colletti M, Khalaileh A, Van den Steen G, et al. Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia. Gut. 2012;61:1723-32 pubmed publisher
    ..In this study, the role of the ductal transcription factors hepatocyte nuclear factor 6 (HNF6, also known as Onecut1) and SRY-related HMG box factor 9 (Sox9) in ADM was investigated.
  21. Jacquemin P, Durviaux S, Jensen J, Godfraind C, Gradwohl G, Guillemot F, et al. Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine gene ngn3. Mol Cell Biol. 2000;20:4445-54 pubmed
    b>Hepatocyte nuclear factor 6 (HNF-6) is the prototype of a new class of cut homeodomain transcription factors...
  22. Lannoy V, Burglin T, Rousseau G, Lemaigre F. Isoforms of hepatocyte nuclear factor-6 differ in DNA-binding properties, contain a bifunctional homeodomain, and define the new ONECUT class of homeodomain proteins. J Biol Chem. 1998;273:13552-62 pubmed
  23. Landry C, Clotman F, Hioki T, Oda H, Picard J, Lemaigre F, et al. HNF-6 is expressed in endoderm derivatives and nervous system of the mouse embryo and participates to the cross-regulatory network of liver-enriched transcription factors. Dev Biol. 1997;192:247-57 pubmed
  24. Lemaigre F, Durviaux S, Truong O, Lannoy V, Hsuan J, Rousseau G. Hepatocyte nuclear factor 6, a transcription factor that contains a novel type of homeodomain and a single cut domain. Proc Natl Acad Sci U S A. 1996;93:9460-4 pubmed
    ..We describe here the mammalian prototype of a sixth family, which we therefore call hepatocyte nuclear factor 6 (HNF-6). It activates the promoter of a gene involved in the control of glucose metabolism...
  25. Samadani U, Costa R. The transcriptional activator hepatocyte nuclear factor 6 regulates liver gene expression. Mol Cell Biol. 1996;16:6273-84 pubmed
    ..These studies suggest that HNF-6 may regulate hepatocyte-specific genes and may play a role in epithelial cell differentiation of gut endoderm via regulation of HNF-3(beta). ..
  26. Odom D, Zizlsperger N, Gordon D, Bell G, Rinaldi N, Murray H, et al. Control of pancreas and liver gene expression by HNF transcription factors. Science. 2004;303:1378-81 pubmed
    ..Our results suggest how misregulation of HNF4alpha can contribute to type 2 diabetes. ..
  27. Rausa F, Hughes D, Costa R. Stability of the hepatocyte nuclear factor 6 transcription factor requires acetylation by the CREB-binding protein coactivator. J Biol Chem. 2004;279:43070-6 pubmed
    We previously demonstrated that the formation of complexes between the DNA binding domains of the hepatocyte nuclear factor 6 (HNF6) and Forkhead Box a2 (Foxa2) transcription factors resulted in synergistic transcriptional activation of ..
  28. Wang M, Chen M, Zheng G, Dillard B, Tallarico M, Ortiz Z, et al. Transcriptional activation by growth hormone of HNF-6-regulated hepatic genes, a potential mechanism for improved liver repair during biliary injury in mice. Am J Physiol Gastrointest Liver Physiol. 2008;295:G357-66 pubmed publisher
    ..This was associated with enhanced serum albumin levels. In conclusion, the GH/HNF-6 axis is a potential in vivo mechanism underlying GH diverse function in the liver to modulate the liver repair response to BDL...
  29. Blaas L, Kornfeld J, Schramek D, Musteanu M, Zollner G, Gumhold J, et al. Disruption of the growth hormone--signal transducer and activator of transcription 5--insulinlike growth factor 1 axis severely aggravates liver fibrosis in a mouse model of cholestasis. Hepatology. 2010;51:1319-26 pubmed publisher
    ..expression of important hepatoprotective genes, such as epidermal growth factor receptor (Egfr), hepatocyte nuclear factor 6 (Hnf6), prolactin receptor (Prlr), and leukemia inhibitory factor receptor (Lifr) as well as increased ..
  30. Costa R, Kalinichenko V, Holterman A, Wang X. Transcription factors in liver development, differentiation, and regeneration. Hepatology. 2003;38:1331-47 pubmed
  31. Geng H, Xiao Q, Xu D, Hu L, Ding K. [Effect of a recombinant lentiviral vector carrying hepatocyte nuclear factor 6 gene on migration and invasion abilities of SW620 cells]. Nan Fang Yi Ke Da Xue Xue Bao. 2012;32:66-70 pubmed
    To construct a recombinant lentiviral vector that stably express hepatocyte nuclear factor 6 (HNF6) in colorectal cancer cell line and examine its effects on the invasive ability of SW620 cells...
  32. Haworth K, Latinkic B. Expression of Xenopus tropicalis HNF6/Onecut-1. Int J Dev Biol. 2009;53:159-62 pubmed publisher
    ..Expression of the Xenopus tropicalis Onecut-1/HNF6 gene was found to be conserved in the neural tube, the sensory placodes and in the anterior ventral endoderm in a domain consistent with the developing liver primordium. ..
  33. Møller A, Ek J, Durviaux S, Urhammer S, Clausen J, Eiberg H, et al. Hepatocyte nuclear factor-6: associations between genetic variability and type II diabetes and between genetic variability and estimates of insulin secretion. Diabetologia. 1999;42:1011-6 pubmed
    ..Mutations in the coding region of the HNF-6 gene are not associated with Type II diabetes or with changes in insulin responses to glucose among the Caucasians examined. ..
  34. Ramirez M, Zubeldia Brenner L, Wargon V, Ornstein A, Becu Villalobos D. Expression and methylation status of female-predominant GH-dependent liver genes are modified by neonatal androgenization in female mice. Mol Cell Endocrinol. 2014;382:825-34 pubmed publisher
    ..Therefore, early steroid treatment or eventually endocrine disruptor exposure may alter methylation status and sexual dimorphic expression of liver genes, and consequently modify liver physiology in females. ..
  35. Kim I, Zhou Y, Ramakrishna S, Hughes D, Solway J, Costa R, et al. Functional characterization of evolutionarily conserved DNA regions in forkhead box f1 gene locus. J Biol Chem. 2005;280:37908-16 pubmed
    ..3-kb Foxf1 promoter in cotransfection assays. These studies demonstrated that the conserved Foxf1 3'RE region is essential for proper tissue-specific regulation of the Foxf1 promoter region during mouse embryogenesis. ..
  36. Hunter M, Wilson C, Jiang X, Cong R, Vasavada H, Kaestner K, et al. The homeobox gene Hhex is essential for proper hepatoblast differentiation and bile duct morphogenesis. Dev Biol. 2007;308:355-67 pubmed
    ..The altered expression of Hnf4alpha, Hnf6 and Hnf1beta in Hhex conditional null mice suggests that Hhex is an essential component of the genetic networks regulating hepatoblast differentiation and intrahepatic bile duct morphogenesis. ..
  37. Matthews R, Plumb Rudewiez N, Lorent K, Gissen P, Johnson C, Lemaigre F, et al. Zebrafish vps33b, an ortholog of the gene responsible for human arthrogryposis-renal dysfunction-cholestasis syndrome, regulates biliary development downstream of the onecut transcription factor hnf6. Development. 2005;132:5295-306 pubmed
    ..Furthermore, they show that tissue-specific roles for genes that regulate trafficking of intracellular proteins have been modified during vertebrate evolution. ..
  38. Kanetsuna Y, Hirano K, Nagata M, Gannon M, Takahashi K, Harris R, et al. Characterization of diabetic nephropathy in a transgenic model of hypoinsulinemic diabetes. Am J Physiol Renal Physiol. 2006;291:F1315-22 pubmed
    ..Thus the HNF6 mouse exhibits diabetic renal changes that parallel the early phase of human DN. The model should facilitate studies of genetic and environmental factors that may affect DN in hypoinsulinemic diabetes. ..
  39. Jacquemin P, Yoshitomi H, Kashima Y, Rousseau G, Lemaigre F, Zaret K. An endothelial-mesenchymal relay pathway regulates early phases of pancreas development. Dev Biol. 2006;290:189-99 pubmed
  40. Ramirez M, Bourguignon N, Bonaventura M, Lux Lantos V, Libertun C, Becu Villalobos D. Neonatal xenoestrogen exposure alters growth hormone-dependent liver proteins and genes in adult female rats. Toxicol Lett. 2012;213:325-31 pubmed publisher
    ..Our findings indicate that perinatal exposure to BPA may compromise the sexually dimorphic capacity of the liver to metabolize drugs and steroids. ..
  41. Alizadeh E, Zarghami N, Eslaminejad M, Akbarzadeh A, Barzegar A, Mohammadi S. The effect of dimethyl sulfoxide on hepatic differentiation of mesenchymal stem cells. Artif Cells Nanomed Biotechnol. 2016;44:157-64 pubmed publisher
    ..05) in DMSO-treated groups. DMSO catalyzes hepatic differentiation; therefore, using DMSO for acceleration of the hepatogenic protocols of AT-MSCs appears advantageous. ..
  42. Clotman F, Libbrecht L, Gresh L, Yaniv M, Roskams T, Rousseau G, et al. Hepatic artery malformations associated with a primary defect in intrahepatic bile duct development. J Hepatol. 2003;39:686-92 pubmed
    ..A primary defect in biliary epithelial cells is associated with hepatic artery malformations in mice. Our data provide a model to interpret and study hepatic artery anomalies in humans. ..
  43. Laudadio I, Manfroid I, Achouri Y, Schmidt D, Wilson M, Cordi S, et al. A feedback loop between the liver-enriched transcription factor network and miR-122 controls hepatocyte differentiation. Gastroenterology. 2012;142:119-29 pubmed publisher
    ..These findings could lead to methods to induce differentiation of hepatocytes in vitro and improve our understanding of liver cell dedifferentiation in pathologic conditions. ..
  44. Wu F, Sapkota D, Li R, Mu X. Onecut 1 and Onecut 2 are potential regulators of mouse retinal development. J Comp Neurol. 2012;520:952-69 pubmed publisher
    ..Furthermore, we showed that Oc1 and Oc2 were expressed in both developing and mature horizontal cells (HCs). Therefore the two factors may also function in the genesis and maintenance of HCs. ..
  45. Wilding L, Gannon M. The role of pdx1 and HNF6 in proliferation and differentiation of endocrine precursors. Diabetes Metab Res Rev. 2004;20:114-23 pubmed
  46. Sheng W, Yan H, Rausa F, Costa R, Liao X. Structure of the hepatocyte nuclear factor 6alpha and its interaction with DNA. J Biol Chem. 2004;279:33928-36 pubmed
    b>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...
  47. Laz E, Sugathan A, Waxman D. Dynamic in vivo binding of STAT5 to growth hormone-regulated genes in intact rat liver. Sex-specific binding at low- but not high-affinity STAT5 sites. Mol Endocrinol. 2009;23:1242-54 pubmed publisher
  48. Chappell L, Gorman S, Campbell F, Ellard S, Rice G, Dobbie A, et al. A further example of a distinctive autosomal recessive syndrome comprising neonatal diabetes mellitus, intestinal atresias and gall bladder agenesis. Am J Med Genet A. 2008;146A:1713-7 pubmed publisher
  49. Yokouchi Y. [Transcription factors regulate various processes of liver development]. Tanpakushitsu Kakusan Koso. 2007;52:133-8 pubmed
  50. Nacer Cherif H, Bois Joyeux B, Rousseau G, Lemaigre F, Danan J. Hepatocyte nuclear factor-6 stimulates transcription of the alpha-fetoprotein gene and synergizes with the retinoic-acid-receptor-related orphan receptor alpha-4. Biochem J. 2003;369:583-91 pubmed
    ..Thus expression of the afp gene requires functional interactions between HNF-6 molecules and between HNF-6 and RORalpha. ..
  51. Lüdtke T, Christoffels V, Petry M, Kispert A. Tbx3 promotes liver bud expansion during mouse development by suppression of cholangiocyte differentiation. Hepatology. 2009;49:969-78 pubmed publisher
    ..Tbx3 controls liver bud expansion by suppressing cholangiocyte and favoring hepatocyte differentiation in the liver bud. ..
  52. Fabris L, Cadamuro M, Libbrecht L, Raynaud P, Spirli C, Fiorotto R, et al. Epithelial expression of angiogenic growth factors modulate arterial vasculogenesis in human liver development. Hepatology. 2008;47:719-28 pubmed
  53. Khoo M, McQuade L, Smith M, Lees J, Sidhu K, Tuch B. Growth and differentiation of embryoid bodies derived from human embryonic stem cells: effect of glucose and basic fibroblast growth factor. Biol Reprod. 2005;73:1147-56 pubmed