Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 600288

FORKHEAD BOX A2; FOXA2

Alternative titles; symbols

HEPATOCYTE NUCLEAR FACTOR 3-BETA; HNF3B

HGNC Approved Gene Symbol: FOXA2

Cytogenetic location: 20p11.21 Genomic coordinates (GRCh38) : 20:22,580,998-22,585,490 (from NCBI)

TEXT

Description

The hepatocyte nuclear factors (see HNF1A, 142410) are transcriptional activators for liver-specific transcripts such as albumin and transthyretin. The HNF3 family, including HNF3A (FOXA1; 602294), HNF3B, and HNF3G (602295), are members of the forkhead class of DNA-binding proteins (Kaestner et al., 1994).

Cloning and Expression

Kaestner et al. (1994) cloned the mouse Hnf3a, Hnf3b, AND Hnf3g genes. The genes encode polypeptides of 468, 459, and 354 amino acids, respectively. Both Hnf3a and Hnf3b are expressed in tissues of endodermal origin, i.e., stomach, intestines, liver, and lung, whereas Hnf3g is more extensively expressed, being present additionally in ovary, testis, heart, and adipose tissue, but missing from lung.

Gene Function

Odom et al. (2007) analyzed the binding of FOXA2, HNF1A, HNF4A (600281), and HNF6 (604164) 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.

Bochkis et al. (2008) found that expression of FOXA2 was virtually undetectable in 2 individuals with primary sclerosing cholangitis (see 109720) and 4 individuals with biliary atresia compared with controls. They suggested that reduced FOXA2 abundance could exacerbate injury in cholestatic diseases.

Gao et al. (2008) found that Foxa1 and Foxa2 co-occupied multiple regulatory domains in the mouse Pdx1 (IPF1; 600733) gene, which is required for pancreatic development. Compound conditional ablation of both Foxa1 and Foxa2 in mouse pancreatic primordium resulted in complete loss of Pdx1 expression, severe pancreatic hypoplasia, disrupted acinar and islet development, hyperglycemia, and death shortly after birth. Foxa1 and Foxa2 predominantly occupied a distal enhancer over 6-kb upstream of the transcriptional start site in the Pdx1 gene, and their occupation of the proximal Pdx1 enhancer was developmentally regulated. Gao et al. (2008) concluded that regulation of PDX1 by FOXA1 and FOXA2 is a key early event controlling expansion and differentiation of the pancreatic primordia.

Silva et al. (2009) showed that Foxa2, a downstream target of insulin signaling, regulates the expression of orexin (602358) and melanin-concentrating hormone (MCH; 176795). During fasting, Foxa2 binds to MCH and orexin promoters and stimulates their expression. In fed and in hyperinsulinemic obese mice, insulin signaling led to nuclear exclusion of Foxa2 and reduced expression of MCH and orexin. Constitutive activation of Foxa2 in the brain resulted in increased neuronal MCH and orexin expression and increased food consumption, metabolism, and insulin sensitivity. Spontaneous physical activity of these animals in the fed state was significantly increased and was similar to that in fasted mice. Conditional activation of Foxa2 through the T156A mutation expression in the brain of obese mice also resulted in improved glucose homeostasis, decreased fat, and increased lean body mass. Silva et al. (2009) concluded that Foxa2 can act as a metabolic sensor in neurons of the lateral hypothalamic area to integrate metabolic signals, adaptive behavior, and physiologic responses.

Sekiya and Suzuki (2011) screened the effects of 12 candidate factors to identify 3 specific combinations of 2 transcription factors, comprising Hnf4-alpha (600281) plus Foxa1, Foxa2, or Foxa3 (602295), that can convert mouse embryonic and adult fibroblasts into cells that closely resemble hepatocytes in vitro. The induced hepatocyte-like (iHep) cells had multiple hepatocyte-specific features and reconstituted damaged hepatic tissues after transplantation.

Li et al. (2012) noted that hepatocellular carcinoma (HCC; 114550) is sexually dimorphic in both rodents and humans, with significantly higher incidence in males due to differences in sex hormones. They identified SNPs in FOXA2-binding sites that resulted in reduced binding of both FOXA2 and estrogen receptor (ESR1; 133430) to their targets, including FGL1 (605776), BTG1 (109580), ABCC4 (605250), and PPM1L (611931), in human liver. Immunoblot analysis showed reduced PPM1L expression and increased FGL1, BTG1, and ABCC4 expression in HCC female livers compared with normal female livers. Li et al. (2012) proposed that impaired regulation of FOXA2 and ESR1 contributes to altered expression of these dual-target genes in HCC and that SNPs in FOXA2-binding sites may contribute to HCC risk in women.

Donaghey et al. (2018) examined genomic occupancy of FOXA2 at endogenously bound cis-regulatory elements across multiple human cell types and found that FOXA2 genomic occupancy was cell-type specific and restricted to a subset of loci containing its preferred core regulatory motif. A low level of FOXA2 enrichment was found in all cells endogenously expressing FOXA2. Analysis of immortalized foreskin fibroblasts, which do not endogenously express FOXA2, showed that ectopic FOXA2 expression did not lead to higher enrichment at most of the endogenous target sites, with little overlap between endogenous and ectopic FOXA2 for most regions occupied by FOXA2 in alternative cell lines. Low-level FOXA2 enrichment was also a feature of cells ectopically expressing FOXA2. These results indicated that the preexisting epigenome must affect FOXA2 binding. Further analysis revealed that cell type-specific binding was influenced by additional cofactors, as GATA4 (600576) coexpression increased FOXA2 enrichment at sites investigated. Analysis of the transcriptional and epigenetic effects of ectopic FOXA2 binding demonstrated that FOXA2 occupancy induced DNA methylation and changed DNA accessibility. Moreover, these changes were not dependent on DNA replication, but the subsequent removal of DNA methylation was dependent on DNA replication.

Mapping

Avraham et al. (1992) mapped the mouse hepatic nuclear factor-3-beta gene to mouse chromosome 2. By homology, the human gene maps to chromosome 20 (Deleuze et al., 1994).

Mincheva et al. (1997) used fluorescence in situ hybridization to map the HNF3B gene to human chromosome 20p11.

Animal Model

Using conditional gene ablation, Sund et al. (2001) generated mice lacking Foxa2 specifically in pancreatic beta cells. The mutant mice were severely hypoglycemic and showed dysregulated secretion of insulin in response to both glucose and amino acids, including hypersecretion of insulin in response to hypoglycemia. In vitro perifusion assays of minced pancreas demonstrated abnormal insulin and glucagon secretion. In mutant islets, mRNA levels for genes encoding both subunits of the K(ATP) channel, SUR1 (ABCC8; 600509) and Kir6.2 (KCNJ11; 600937), were reduced by 81% and 73%, respectively. Sund et al. (2001) noted that ABCC8 and KCNJ11 are the most frequently mutated genes in familial hyperinsulinemic hypoglycemia (see HHF1; 256450) and suggested human FOXA2 as a candidate gene for that disorder. In isolated pancreatic islets from mice lacking Foxa2 specifically in beta cells, Lantz et al. (2004) observed excessive insulin release in response to amino acids and complete loss of glucose-stimulated insulin secretion. By RNA in situ hybridization with digoxigenin-labeled antisense probes, they showed that transcripts of Abcc8 and Kcnj11 were undetectable in Foxa2-null beta cells. Foxa2-null beta cells did not respond to glyburide, indicating lack of functional K(ATP) channels. Expression profiling identified the Hadh gene (601609), mutation in which causes hyperinsulinemic hypoglycemia (HHF4; 609975) in humans, as an additional target of Foxa2. By coimmunoprecipitation and cotransfection studies, they showed that Foxa2 bound Had and activated transcription by up to a 3-fold increase. Lantz et al. (2004) concluded that FOXA2 is an essential activator of genes that function in multiple pathways governing insulin secretion.

Wolfrum et al. (2003) demonstrated that Foxa2 is expressed in preadipocytes and induced de novo in adipocytes of genetic and diet-induced mouse models of obesity. In preadipocytes, Foxa2 inhibited adipocyte differentiation by activating transcription of preadipocyte factor-1 (DLK1; 176290); expression of both Foxa2 and Dlk1 was enhanced by growth hormone (GH1; 139250). In differentiated adipocytes, Foxa2 expression induced multiple genes involved in glucose and fat metabolism. Diet-induced obese Foxa2 +/- mice developed increased adiposity compared to controls, and their adipocytes exhibited defects in glucose uptake and metabolism. Wolfrum et al. (2003) suggested that Foxa2 plays an important role as a physiologic regulator of adipocyte differentiation and metabolism.

Wolfrum et al. (2004) demonstrated that in normal mice, plasma insulin (176730) inhibits Foxa2 by nuclear exclusion and that in the fasted (low insulin) state Foxa2 activates transcriptional programs of lipid metabolism and ketogenesis. In insulin-resistant or hyperinsulinemic mice, Foxa2 is inactive and permanently located in the cytoplasm of hepatocytes. In these mice, adenoviral expression of Foxa2T156A, a nuclear, constitutively active Foxa2 that cannot be inhibited by insulin (Wolfrum et al., 2003), decreases hepatic triglyceride content, increases hepatic insulin sensitivity, reduces glucose production, normalizes plasma glucose, and significantly lowers plasma insulin. These changes are associated with increased expression of genes encoding enzymes of fatty acid oxidation, ketogenesis, and glycolysis. Wolfrum et al. (2004) concluded that chronic hyperinsulinemia in insulin-resistant syndromes results in the cytoplasmic localization and inactivation of Foxa2, thereby promoting lipid accumulation and insulin resistance in the liver.

Lee et al. (2005) showed that Foxa1 (602294) and Foxa2 are required in concert for hepatic specification in mouse. In embryos deficient for both genes in the foregut endoderm, no liver bud was evident and expression of the hepatoblast marker alpha-fetoprotein (AFP; 104150) was lost. Furthermore, Foxa1/Foxa2-deficient endoderm cultured in the presence of exogenous fibroblast growth factor-2 (FGF2; 134920) failed to initiate the expression of the liver markers albumin and transthyretin (176300). Thus, Lee et al. (2005) concluded that Foxa1 and Foxa2 are required for the establishment of competence within the foregut endoderm and the onset of hepatogenesis.

Using a conditional knockout model to eliminate Foxa1 and Foxa2 in liver after initial hepatic specification in mouse embryos, Li et al. (2009) found that Foxa1 and Foxa2 were required for bile duct formation at a later stage of liver development. In the absence of Foxa1 and Foxa2, embryonic liver showed hyperplasia of the biliary tree that was due, at least in part, to activation of Il6 (147620) expression, a proliferative signal for cholangiocytes.

Bochkis et al. (2008) found that hepatocyte-specific Foxa2 deletion in mice led to decreased transcription of genes encoding bile acid transporters on both the basolateral and canalicular membranes, resulting in intrahepatic cholestasis. Foxa2-deficient mice were highly sensitive to a diet containing cholic acid, which resulted in toxic accumulation of hepatic bile salts, endoplasmic reticulum stress, and liver injury.

Wolfrum et al. (2008) observed a 4-fold decrease in plasma mRNA and protein levels of Apom (606907), but not other apolipoproteins, in hyperinsulinemic and obese mice compared with nonobese wildtype mice. Analysis of hepatocytes from these mice showed that decreased Apom levels were dependent on increased insulin levels and were associated with localization of Foxa2 to cytosol. Further analysis showed that Foxa2 also regulated plasma high density lipoprotein (HDL) levels and that insulin and Pik3ca (171834) transcriptionally regulated Apom via Foxa2. Haploinsufficient Foxa2 +/- mice exhibited decreased hepatic Apom expression and plasma pre-beta-HDL and HDL levels. Apom -/- mice did not show increased plasma HDL levels, even with expression of constitutively active Foxa2. Wolfrum et al. (2008) concluded that their findings revealed a mechanism by which insulin regulates plasma HDL levels in physiologic and insulin-resistant states.

Li et al. (2012) found that diethylnitrosamine induced liver cancer in both male and female mice with liver-specific deletion of Foxa1 and Foxa2. Coregulation of target genes by Foxa1 and Foxa2 and either Esr1 or androgen receptor (AR; 313700) was increased during hepatocarcinogenesis in normal female or male mice, respectively, but was lost in Foxa1/Foxa2-deficient mice. Li et al. (2012) concluded that both estrogen-dependent resistance and androgen-mediated facilitation of HCC depend on FOXA1 and FOXA2.

Kelleher et al. (2017) conditionally deleted Foxa2 in adult and neonatal mouse uteri and found that adult uteri were morphologically normal and contained uterine glands, whereas uteri of neonatal mice lacked glands. Adult mice were infertile due to defects in blastocyst implantation and stromal cell decidualization. Lif (159540), a factor derived from uterine glands, was not expressed during early pregnancy in adult mutant mice. Injection of Lif initiated blastocyst implantation in uteri of both gland-containing and glandless adult Foxa2-deleted mice. Although pregnancy was rescued by Lif and maintained to term in uterine gland-containing adult Foxa2-deficient mice, it failed by day 10 in neonatal Foxa2-deleted mice lacking glands. Kelleher et al. (2017) concluded that FOXA2 has a role in regulation of adult uterine function and fertility, and that uterine glands and their secretions have important roles in blastocyst implantation and stromal cell decidualization.

REFERENCES

  1. Avraham, K. B., Prezioso, V. R., Chen, W. S., Lai, E., Sladek, F. M., Zhong, W., Darnell, J. E., Jr., Jenkins, N. A., Copeland, N. G.Murine chromosomal location of four hepatocyte-enriched transcription factors: HNF-3-alpha, HNF-3-beta, HNF-3-gamma, and HNF-4. Genomics 13: 264-268, 1992. [PubMed: 1612587] [Full Text: https://doi.org/10.1016/0888-7543(92)90241-j\]
  2. Bochkis, I. M., Rubins, N. E., White, P., Furth, E. E., Friedman, J. R., Kaestner, K. H.Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and results in endoplasmic reticulum stress. Nature Med. 14: 828-836, 2008. [PubMed: 18660816] [Full Text: https://doi.org/10.1038/nm.1853\]
  3. Deleuze, J. F., Dhorne, S., Hazan, J., Borghi, E., Raynaud, N., Pollet, N., Meunier-Rotival, M., Deschatrette, J., Alagille, D., Hadchouel, M.Deleted chromosome 20 from a patient with Alagille syndrome isolated in a cell hybrid through leucine transport selection: study of three candidate genes. Mammalian Genome 5: 663-669, 1994. [PubMed: 7873876] [Full Text: https://doi.org/10.1007/BF00426072\]
  4. Donaghey, J., Thakurela, S., Charlton, J., Chen, J. S., Smith, Z. D., Gu, H., Pop, R., Clement, K., Stamenova, E. K., Karnik, R., Kelley, D. R., Gifford, C. A., Cacchiarelli, D., Rinn, J. L., Gnirke, A., Ziller, M. J., Meissner, A.Genetic determinants and epigenetic effects of pioneer-factor occupancy. Nature Genet. 50: 250-258, 2018. [PubMed: 29358654] [Full Text: https://doi.org/10.1038/s41588-017-0034-3\]
  5. Gao, N., LeLay, J., Vatamaniuk, M. Z., Rieck, S., Friedman, J. R., Kaestner, K. H.Dynamic regulation of Pdx1 enhancers by Foxa1 and Foxa2 is essential for pancreas development. Genes Dev. 22: 3435-3448, 2008. [PubMed: 19141476] [Full Text: https://doi.org/10.1101/gad.1752608\]
  6. Kaestner, K. H., Hiemisch, H., Luckow, B., Schutz, G.The HNF-3 gene family of transcription factors in mice: gene structure, cDNA sequence, and mRNA distribution. Genomics 20: 377-385, 1994. [PubMed: 8034310] [Full Text: https://doi.org/10.1006/geno.1994.1191\]
  7. Kelleher, A. M., Peng, W., Pru, J. K., Pru, C. A., DeMayo, F. J., Spencer, T. E.Forkhead box a2 (FOXA2) is essential for uterine function and fertility. Proc. Nat. Acad. Sci. 114: E1018-E1026, 2017. [PubMed: 28049832] [Full Text: https://doi.org/10.1073/pnas.1618433114\]
  8. Lantz, K. A., Vatamaniuk, M. Z., Brestelli, J. E., Friedman, J. R., Matschinsky, F. M., Kaestner, K. H.Foxa2 regulates multiple pathways of insulin secretion. J. Clin. Invest. 114: 512-520, 2004. [PubMed: 15314688] [Full Text: https://doi.org/10.1172/JCI21149\]
  9. Lee, C. S., Friedman, J. R., Fulmer, J. T., Kaestner, K. H.The initiation of liver development is dependent on Foxa transcription factors. (Letter) Nature 435: 944-947, 2005. [PubMed: 15959514] [Full Text: https://doi.org/10.1038/nature03649\]
  10. Li, Z., Tuteja, G., Schug, J., Kaestner, K. H.Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. Cell 148: 72-83, 2012. [PubMed: 22265403] [Full Text: https://doi.org/10.1016/j.cell.2011.11.026\]
  11. Li, Z., White, P., Tuteja, G., Rubins, N., Sackett, S., Kaestner, K. H.Foxa1 and Foxa2 regulate bile duct development in mice. J. Clin. Invest. 119: 1537-1545, 2009. [PubMed: 19436110] [Full Text: https://doi.org/10.1172/JCI38201\]
  12. Mincheva, A., Lichter, P., Schutz, G., Kaestner, K. H.Assignment of the human genes for hepatocyte nuclear factor 3-alpha, -beta, and -gamma (HNF3A, HNF3B, HNF3G) to 14q12-q13, 20p11, and 19q13.2-q13.4. Genomics 39: 417-419, 1997. [PubMed: 9119385] [Full Text: https://doi.org/10.1006/geno.1996.4477\]
  13. 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\]
  14. Sekiya, S., Suzuki, A.Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature 475: 390-393, 2011. [PubMed: 21716291] [Full Text: https://doi.org/10.1038/nature10263\]
  15. Silva, J. P., von Meyenn, F., Howell, J., Thorens, B., Wolfrum, C., Stoffel, M.Regulation of adaptive behaviour during fasting by hypothalamic Foxa2. Nature 462: 646-650, 2009. [PubMed: 19956259] [Full Text: https://doi.org/10.1038/nature08589\]
  16. Sund, N. J., Vatamaniuk, M. Z., Casey, M., Ang, S.-L., Magnuson, M. A., Stoffers, D. A., Matschinsky, F. M., Kaestner, K. H.Tissue-specific deletion of Foxa2 in pancreatic beta cells results in hyperinsulinemic hypoglycemia. Genes Dev. 15: 1706-1715, 2001. [PubMed: 11445544] [Full Text: https://doi.org/10.1101/gad.901601\]
  17. Wolfrum, C., Asilmaz, E., Luca, E., Friedman, J. M., Stoffel, M.Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes. Nature 432: 1027-1032, 2004. [PubMed: 15616563] [Full Text: https://doi.org/10.1038/nature03047\]
  18. Wolfrum, C., Besser, D., Luca, E., Stoffel, M.Insulin regulates the activity of forkhead transcription factor Hnf-3-beta/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization. Proc. Nat. Acad. Sci. 100: 11624-11629, 2003. [PubMed: 14500912] [Full Text: https://doi.org/10.1073/pnas.1931483100\]
  19. Wolfrum, C., Howell, J. J., Ndungo, E., Stoffel, M.Foxa2 activity increases plasma high density lipoprotein levels by regulating apolipoprotein M. J. Biol. Chem. 283: 16940-16949, 2008. [PubMed: 18381283] [Full Text: https://doi.org/10.1074/jbc.M801930200\]
  20. Wolfrum, C., Shih, D. Q., Kuwajima, S., Norris, A. W., Kahn, C. R., Stoffel, M.Role of Foxa-2 in adipocyte metabolism and differentiation. J. Clin. Invest. 112: 345-356, 2003. [PubMed: 12865419] [Full Text: https://doi.org/10.1172/JCI18698\]

Contributors:

Bao Lige - updated : 08/07/2018
Paul J. Converse - updated : 07/14/2017
Ada Hamosh - updated : 8/4/2011
Patricia A. Hartz - updated : 12/2/2010
Ada Hamosh - updated : 1/6/2010
Patricia A. Hartz - updated : 3/6/2009
Patricia A. Hartz - updated : 8/15/2008
Patricia A. Hartz - updated : 8/3/2007
Marla J. F. O'Neill - updated : 3/30/2006
Ada Hamosh - updated : 9/7/2005
Ada Hamosh - updated : 3/3/2005
Marla J. F. O'Neill - updated : 2/18/2005
Jennifer P. Macke - updated : 2/4/1998

Creation Date:

Victor A. McKusick : 1/6/1995

Edit History:

mgross : 08/07/2018
mgross : 07/14/2017
mgross : 07/14/2017
mgross : 07/14/2017
mgross : 07/14/2017
mgross : 07/14/2017
carol : 04/15/2014
alopez : 8/15/2011
terry : 8/4/2011
mgross : 12/6/2010
terry : 12/2/2010
alopez : 1/15/2010
terry : 1/6/2010
wwang : 4/29/2009
mgross : 3/6/2009
terry : 3/6/2009
mgross : 8/19/2008
terry : 8/15/2008
alopez : 8/3/2007
carol : 8/16/2006
carol : 7/18/2006
wwang : 4/3/2006
wwang : 3/31/2006
wwang : 3/31/2006
terry : 3/30/2006
alopez : 9/14/2005
terry : 9/7/2005
alopez : 3/3/2005
terry : 3/3/2005
wwang : 2/22/2005
terry : 2/18/2005
tkritzer : 12/10/2002
carol : 9/18/2002
carol : 2/13/1998
carol : 2/4/1998
carol : 1/6/1995