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 SOX9
Homo sapiens
 HIF1A
Homo sapiens
 Pax6
Mus musculus
 PAX6
Homo sapiens
 Snai2
Mus musculus
 PPARA
Homo sapiens
 Ppara
Mus musculus
 Thrb
Mus musculus
 SNAI2
Homo sapiens
 Tbr1
Mus musculus
Transcription Factor Encyclopedia  BETA
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Overview

Forkhead box A1 (Foxa1, HNF3α), Foxa2 (HNF3β), and Foxa3 (HNF3γ) are a group of three closely related transcription factors initially identified in liver cells for their ability to interact with the promoters of the important liver-enriched genes transthyretin (Ttr), alpha 1-antitrypsin (alpha 1-AT), and albumin (Alb) [1][2][3]. The three Foxa family members contain a highly conserved winged-helix DNA-binding domain (also known as forkhead) with a transcriptional activation domain on either side[4] (see figure 1). The 110-amino acid domain is 85% identical between the three proteins but outside of the forkhead domain Foxa1 and Foxa2 are more closely related than Foxa3. In vitro experiments have suggested that all three family members are able to bind to similar DNA sequences, in some cases with different binding affinities[1]; sequences that bind specific family members have been identified[5][6]. Interestingly, in vivo mutational analysis has indicated that Foxa1 and Foxa2 are highly functionally redundant in liver, pancreas, lung and dopaminergic neurons [7].

In the early embryo, Foxa2 is the first Foxa family member to be expressed. During gastrulation, Foxa2 is initially detected in the anterior primitive streak of the E6.5 (embryonic day 6.5) mouse embryo followed by expression in the node, notochord, floorplate of the neural tube and endoderm (reviewed[3]). Foxa1 expression closely follows expression of Foxa2. Foxa3 is the last of the three to be expressed in the embryo with expression detected in the definitive endoderm (the cells that constitute the epithelial precursor cells for all gut organs). Foxa2 is also expressed in the visceral endoderm of the yolk sac.

As embryogenesis proceeds, the Foxa family plays roles in the development and function of many organs including the liver, pancreas, lung, prostate, mammary gland and kidney. In the adult, they control many genes involved in metabolism, fasting response, and blood sugar regulation and homeostasis. In addition, FOXA1 and FOXA2 can regulate the development of dopaminergic neurons [8] and heterozygosity of Foxa2 has been associated with death of these neurons, causing a phenotype similar to Parkinson’s disease [9].

In addition to playing a direct role in transcriptional regulation, the FOXA family members are thought to affect chromatin structure. FOXA proteins can act as pioneer factors by binding to the H3/H4 histones and opening compacted chromatin to allow binding and transcriptional initiation by other transcription factors [10][11][12]. Interestingly, one of the helices of the proteins shows great similarity to the winged-helix domain of the linker histones H1 and H5 [13][14], which are responsible for binding the DNA and the core histones. This domain in the FOXA proteins allows the transcription factor to bind to one side of the nucleosome core and occupy a functional linker histone site[15].

FOXA proteins are the founding members of a large family of transcription factors which share the winged-helix or forkhead domain. All family members are designated as Fox (for Forkhead bOX) with the letter indicating the subgroup within the family. In humans and mouse there are 43 and 42 Fox family members respectively.

Foxa homologs are highly evolutionarily conserved. Between mouse and humans, FOXA1, FOXA2 and FOXA3 are 95.7%, 97.4% and 89.7% identical (from HomoloGene). The Foxa family is represented by a single gene in C. elegans, Pha-4, and in Drosophila, Forkhead (Fkh). Interestingly, the Drosophila Fkh protein shares 48.5% identity with human Foxa2 and 49.1% with mouse Foxa2 and the conservation exceeds 90% in the forkhead domain.

References
  1. Costa RH et al. Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes. Mol. Cell. Biol., 9(4):1415-25. (PMID 2786140)
  2. Herbst RS et al. Differential regulation of hepatocyte-enriched transcription factors explains changes in albumin and transthyretin gene expression among hepatoma cells. New Biol., 3(3):289-96. (PMID 1878351)
  3. Friedman JR and Kaestner KH. The Foxa family of transcription factors in development and metabolism. Cell. Mol. Life Sci., 63(19-20):2317-28. (PMID 16909212)
  4. Pani L et al. Hepatocyte nuclear factor 3 beta contains two transcriptional activation domains, one of which is novel and conserved with the Drosophila fork head protein. Mol. Cell. Biol., 12(9):3723-32. (PMID 1324404)
  5. Samadani U et al. Identification of a transthyretin enhancer site that selectively binds the hepatocyte nuclear factor-3 beta isoform. Gene Expr., 6(1):23-33. (PMID 8931989)
  6. Motallebipour M et al. Differential binding and co-binding pattern of FOXA1 and FOXA3 and their relation to H3K4me3 in HepG2 cells revealed by ChIP-seq. Genome Biol., 10(11):R129. (PMID 19919681)
  7. Lee CS et al. Foxa2 is required for the differentiation of pancreatic alpha-cells. Dev. Biol., 278(2):484-95. (PMID 15680365)
  8. Lin W et al. Foxa1 and Foxa2 function both upstream of and cooperatively with Lmx1a and Lmx1b in a feedforward loop promoting mesodiencephalic dopaminergic neuron development. Dev. Biol., 333(2):386-96. (PMID 19607821)
  1. Kittappa R et al. The foxa2 gene controls the birth and spontaneous degeneration of dopamine neurons in old age. PLoS Biol., 5(12):e325. (PMID 18076286)
  2. Zhang L et al. Foxa2 integrates the transcriptional response of the hepatocyte to fasting. Cell Metab., 2(2):141-8. (PMID 16098831)
  3. Gualdi R et al. Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. Genes Dev., 10(13):1670-82. (PMID 8682297)
  4. Cirillo LA et al. Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Mol. Cell, 9(2):279-89. (PMID 11864602)
  5. Ramakrishnan V et al. Crystal structure of globular domain of histone H5 and its implications for nucleosome binding. Nature, 362(6417):219-23. (PMID 8384699)
  6. Clark KL et al. Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature, 364(6436):412-20. (PMID 8332212)
  7. Cirillo LA et al. Binding of the winged-helix transcription factor HNF3 to a linker histone site on the nucleosome. EMBO J., 17(1):244-54. (PMID 9427758)
Figures
FIGURE 1 Protein domain strucure of FOXAs.
Foxa1/2/3 are highly homologous proteins that interact with DNA as monomers and consist of two N- and C-terminal transactivation domains (TA) and a central forkhead domain. Within the forkhead domain there is 95% sequence homology between the three family members, while the flanking region shows less similarity, particularly for Foxa3. Past the N- and C-terminals of the forkhead domain lie two nuclear localization signals (asterisks). Within the forkhead domain, there are three α-helices (Helix H1-3) and three β-strands (βS1-3). The proteins interact with DNA in three ways: the major grove interacts with Helix H3; the DNA backbone interacts with wing 1 (W1), which the contains β-strands 2 and 3 along with an intermediary loop; and the minor grove is contacted by the less well structured wing2 (W2). Foxa2 alone of the three family members also contains an Akt/PKB phosphorylation site located at T156 (highlighted in red) which may or may not be involved in nuclear localization of the protein (see Friedman and Kaestner, 2006 for a discussion).
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.