Alternative titles; symbols
HGNC Approved Gene Symbol: ONECUT1
Cytogenetic location: 15q21.3 Genomic coordinates (GRCh38) : 15:52,755,053-52,790,336 (from NCBI)
Tissue-specific transcription is regulated in part by cell type-restricted proteins that bind to defined sequences in target genes. The DNA-binding domain of these proteins is often evolutionarily conserved; on this basis, liver-enriched transcription factors have been classified into various families. See, for example, HNF3A (602294) and HNF1A (142410). Lemaigre et al. (1996) isolated from rat liver a transcription factor, which they called hepatocyte nuclear factor-6, that contains 2 different DNA-binding domains: a novel type of homeodomain, and a homolog of the Drosophila cut domain. A similar bipartite sequence had been found only in the genome of Caenorhabditis elegans. The HNF6 cDNA encodes a deduced protein of 465 amino acids. By RNase protection assay, the expression of HNF6 was found to be highest in liver, but was also detectable in brain, spleen, and testis.
By RT-PCR, Jacquemin et al. (1999) determined the tissue distribution of ONECUT1 in 12 human tissues. They found strong ONECUT1 expression in liver and lower expression in testis and skin.
Vaisse et al. (1997) found that all members of the HNF3 family as well as HNF4G (605966) and HNF6 are expressed in pancreatic beta cells. They also identified and characterized simple tandem repeat DNA polymorphisms in all of these genes.
Samadani and Costa (1996) determined that HNF6 activates transcription of the promoters of HNF3B (600288) and TTR (176300). Further studies suggested that HNF6 is important not only for the regulation of a wide variety of genes expressed in hepatocytes and, putatively, intestinal epithelium, but also for the inception of gut endoderm-derived organs via activation of the HNF3B protein.
Glucocorticoids exert their effects on gene transcription through ubiquitous receptors that bind to regulatory sequences present in many genes. These glucocorticoid receptors are present in all cell types, yet glucocorticoid action is controlled in a tissue-specific way. The mechanism for this control relies on tissue-specific transcriptional activators that bind in the vicinity of the glucocorticoid receptor and are required for receptor action. Pierreux et al. (1999) described a gene-specific and tissue-specific inhibitory mechanism through which glucocorticoid action is repressed by a tissue-restricted transcription factor, hepatocyte nuclear factor-6. HNF6 inhibits the glucocorticoid-induced stimulation of 2 genes coding for enzymes of liver glucose metabolism, namely 6-phosphofructo-2 kinase (PFKFB1; 311790) and phosphoenolpyruvate carboxykinase (PCK1; 261680). Binding of HNF6 to DNA is required for inhibition of glucocorticoid receptor activity. In vitro and in vivo experiments suggested that this inhibition is mediated by a direct HNF6/glucocorticoid receptor interaction involving the N-terminal domain of HNF6 and the DNA-binding domain of the receptor. Thus, in addition to its known property of stimulating transcription of liver-expressed genes, HNF6 can antagonize glucocorticoid-stimulated gene transcription.
To gain insight into the transcriptional regulatory networks that specify and maintain human tissue diversity, Odom et al. (2004) used chromatin immunoprecipitation combined with promoter microarrays to identify systematically the genes occupied by the transcriptional regulators HNF1-alpha, HNF4-alpha (600281), and HNF6, together with RNA polymerase II (see 180660), in human liver and pancreatic islets. Odom et al. (2004) identified tissue-specific regulatory circuits formed by HNF1-alpha, HNF4-alpha, and HNF6 with other transcription factors, revealing how these factors function as master regulators of hepatocyte and islet transcription.
Odom et al. (2007) analyzed the binding of HNF3B, HNF1A, HNF4A, and HNF6 to 4,000 orthologous gene pairs in hepatocytes purified from human and mouse livers. Despite the conserved function of these factors, 41 to 89% of the binding events seemed to be species-specific. Importantly, the binding sites varied widely between species in ways that could not be predicted from human-mouse sequence alignments alone.
By fluorescence in situ hybridization, Vaisse et al. (1997) mapped the HNF6A gene to 15q21.1-q21.2.
During mouse development, Hnf6 is expressed in the epithelial cells that are precursors of the exocrine and endocrine pancreatic cells. Jacquemin et al. (2000) investigated the role of Hnf6 in pancreas differentiation by inactivating its gene in the mouse. In hnf6-null embryos, the exocrine pancreas appeared to be normal but endocrine cell differentiation was impaired. The expression of neurogenin-3 (NGN3; 604882), a transcription factor that is essential for determination of endocrine cell precursors, was almost abolished. Consistent with this, Jacquemin et al. (2000) demonstrated that Hnf6 binds to and stimulates the ngn3 gene promoter. At birth, only a few endocrine cells were found and the islets of Langerhans were missing. Later, the number of endocrine cells increased and islets appeared. However, the architecture of the islets was perturbed, and the beta cells were deficient in glucose transporter-2 (SLC2A2; 138160) expression. Adult hnf6-null mice were diabetic. The authors concluded that Hnf6 controls pancreatic endocrine differentiation at the precursor stage and stated that their data identify Hnf6 as the first positive regulator of the proendocrine gene ngn3 in the pancreas.
During pancreatic organogenesis, endocrine cells arise from non-self-renewing progenitors that express Ngn3. Maestro et al. (2003) showed that from E13 to E18 (the embryonic stage during which the major burst of beta-cell neogenesis takes place) murine pancreatic duct cells express Hnf1b (189907), the product of the maturity-onset diabetes of the young type-5 (MODY5; 137920) gene. Ngn3-positive cells at this stage invariably cluster with mitotically competent Hnf1b-positive cells and are often intercalated with these cells in the epithelium that lines the lumen of primitive ducts. Hnf1b expression is markedly reduced in early pancreatic epithelial cells of Hnf6-deficient mice, in which formation of Ngn3-positive cells is defective. Maestro et al. (2003) suggested that Hnf1b plays a role in the genetic hierarchy regulating the generation of pancreatic endocrine cells.
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. Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine gene ngn3. Molec. Cell. Biol. 20: 4445-4454, 2000. [PubMed: 10825208] [Full Text: https://doi.org/10.1128/MCB.20.12.4445-4454.2000]
Jacquemin, P., Lannoy, V. J., Rousseau, G. G., Lemaigre, F. P. 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. 274: 2665-2671, 1999. [PubMed: 9915796] [Full Text: https://doi.org/10.1074/jbc.274.5.2665]
Lemaigre, F. P., Durviaux, S. M., Truong, O., Lannoy, V. J., Hsuan, J. J., Rousseau, G. G. Hepatocyte nuclear factor 6, a transcription factor that contains a novel type of homeodomain and a single cut domain. Proc. Nat. Acad. Sci. 93: 9460-9464, 1996. [PubMed: 8790352] [Full Text: https://doi.org/10.1073/pnas.93.18.9460]
Maestro, M. A., Boj, S. F., Luco, R. F., Pierreux, C. E., Cabedo, J., Servitja, J. M., German, M. S., Rousseau, G. G., Lemaigre, F. P., Ferrer, J. Hnf6 and Tcf2 (MODY5) are linked in a gene network operating in a precursor cell domain of the embryonic pancreas. Hum. Molec. Genet. 12: 3307-3314, 2003. [PubMed: 14570708] [Full Text: https://doi.org/10.1093/hmg/ddg355]
Odom, D. T., Dowell, R. D., Jacobsen, E. S., Gordon, W., Danford, T. W., MacIsaac, K. D., Rolfe, P. A., Conboy, C. M., Gifford, D. K., Fraenkel, E. Tissue-specific transcriptional regulation has diverged significantly between human and mouse. Nature Genet. 39: 730-732, 2007. [PubMed: 17529977] [Full Text: https://doi.org/10.1038/ng2047]
Odom, D. T., Zizlsperger, N., Gordon, D. B., Bell, G. W., Rinaldi, N. J., Murray, H. L., Volkert, T. L., Schreiber, J., Rolfe, P. A., Gifford, D. K., Fraenkel, E., Bell, G. I., Young, R. A. Control of pancreas and liver gene expression by HNF transcription factors. Science 303: 1378-1381, 2004. [PubMed: 14988562] [Full Text: https://doi.org/10.1126/science.1089769]
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. Antiglucocorticoid activity of hepatocyte nuclear factor-6. Proc. Nat. Acad. Sci. 96: 8961-8966, 1999. [PubMed: 10430878] [Full Text: https://doi.org/10.1073/pnas.96.16.8961]
Samadani, U., Costa, R. H. The transcriptional activator hepatocyte nuclear factor 6 regulates liver gene expression. Molec. Cell. Biol. 16: 6273-6284, 1996. [PubMed: 8887657] [Full Text: https://doi.org/10.1128/MCB.16.11.6273]
Vaisse, C., Kim, J., Espinosa, R., III, Le Beau, M. M., Stoffel, M. Pancreatic islet expression studies and polymorphic DNA markers in the genes encoding hepatocyte nuclear factor-3-alpha, -3-beta, -4-gamma, and -6. Diabetes 46: 1364-1367, 1997. [PubMed: 9231664] [Full Text: https://doi.org/10.2337/diab.46.8.1364]