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FLASH GENE
Symbol FOXA2 contributors: mct/ - updated : 12-12-2017
HGNC name forkhead box A2
HGNC id 5022
DNA
TYPE functioning gene
STRUCTURE 4.46 kb     3 Exon(s)
10 Kb 5' upstream gene genomic sequence study
MAPPING cloned Y linked N status confirmed
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
2 - 2428 48.3 457 - 2008 17715393
3 - 2415 48.3 457 - 2008 17715393
FOXA2-V2 differs in the 5'UTR compared to FOXA2-V1
EXPRESSION
Type restricted
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Digestiveintestinesmall intestine   
 stomach    
Reproductivefemale systemuteruscervix  
Respiratorylung    
cells
SystemCellPubmedSpeciesStageRna symbol
Endocrineislet cell (alpha,beta...)
Respiratoryepithelial cell
cell lineage
cell lines
fluid/secretion
at STAGE
physiological period embryo
Text visceral, definitive endoderm, endodermal cells, node, notochord, floorplate
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a forkhead (FH, winged helix) domain
  • a FOXA2 DNA-binding domain (FOXA2-DBD) adopts the canonical winged-helix fold, with helix H3 and wing 1 regions mainly mediating the DNA recognition
  • two loops-wings on the C terminal side of helix-turn-helix homeodomain
  • HOMOLOGY
    interspecies homolog to Drosophila homeo forkhead DNA binding domain
    homolog to murine Foxa2
    Homologene
    FAMILY
  • HNF-3 forkhead family of transcriptional activators
  • CATEGORY transcription factor
    SUBCELLULAR LOCALIZATION     plasma membrane,junction
        intracellular
    intracellular,cytoplasm
    intracellular,nucleus,nucleoplasm
    basic FUNCTION
  • activator of gene expression in hepatocytes (such as albumin and transthyretin), respiratory and intestinal epithelia
  • regulates a complex pulmonary program of epithelial cell maturation required for transition to air breathing at birth
  • important in regulation of prothrombin expression
  • represses transcription of OATP8
  • regulates 5-aminolevulinate synthase gene expression and is involved in insulin repression
  • may be a novel tumor suppressor gene in lung cancer
  • regulating with nuclear factor 1 the 5-aminolevulinate synthase gene (ALAS1) expression and involved in insulin repression
  • required for cell-specific activation of the glucagon gene in pancreatic islet alpha-cell
  • playing a role in opening the chromatin at the start site of transcription of the glucagon gene
  • playing an important role in MUC2 mucin expression in the intestine during goblet cell differentiation
  • important regulator of MUC2 expression in the intestine
  • regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner
  • cooperate with FOXA1 during liver and lung morphogenesis
  • LMX1A and LMX1B cooperate with FOXA2 to coordinate the specification of dopaminergic neurons and control of floor plate cell differentiation in the developing mesencephalon
  • in melanoma cells, FOXA2 expression is silenced and therefore PI3 is maintained unexpressed to facilitate cell proliferation in the disease melanoma
  • important regulator of glucose and lipid metabolism and organismal energy balance
  • FOXA2, H2AFZ mediate nucleosome depletion during embryonic stem cell differentiation
  • H2AFZ and FOXA2 both act to regulate nucleosome depletion and gene activation, thus promoting ES cell differentiation, whereas DNA methylation promotes nucleosome occupation and suppresses gene expression
  • FOXA1, FOXA2 are required for activation of SHH in the notochord
  • activates lipid metabolism and ketogenesis during fasting and is inhibited via insulin-PI3K-AKT1 signaling-mediated phosphorylation at Thr156 and nuclear exclusion
  • a later role for FOXA1, FOXA2 genes in regulating the maintenance of dopaminergic phenotype in mesodiencephalic dopaminergic (mDA) neurons
  • is a master regulator of endoderm development and pancreatic beta cell gene expression
  • plays a pivotal role in regulating intestinal epithelial cell function
  • promotes cell proliferation, maintains cancer stem cells, favors the development of Triple-Negative/Basal-like tumors, and is associated with increase relapses
  • plays an important in development, cellular metabolism and tumorigenesis
  • plays a crucial role in islet development and endocrine functions
  • plays essential roles in liver development and bile acid homeostasis
  • FOXA2, a Transcription factor controlling pancreas specification, broadly contributed to the cis-regulatory networks of Pancreatic ductal adenocarcinoma (PDAC)
  • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS development
    text required in visceral endoderm for normal primitive streak morphogenesis
    PATHWAY
    metabolism carbohydrate
    signaling
    a component
    INTERACTION
    DNA interacting with chromatin
    RNA
    small molecule
    protein
  • cooperating with GRL to activate genes that code for proteins involved in glucose homeostasis, namely PEPCK (PCK1, PCK2), TAT, IGFBP1, unlikely to be a common cause of NIDDM
  • specific binding of FOXA2 to GFER promoter and this binding was inducible when the cells were simultaneously stimulated with IL6
  • PI3-expression is modulated via epigenetically regulated expression of the transcription factor FOXA2
  • FABP1 is regulated by liver-enriched transcription factors FOXA2 and CEBPA
  • colocalizes with NEUROG3 in pancreatic progenitors, thus indicating a primary role for this factor in regulating NEUROG3 expression
  • FOXA2 acts as a co-activator potentiating expression of the NR4A2-induced dopamine (DA) phenotype via epigenetic regulation
  • FOXA1 and FOXA2 control glucagon biosynthesis and secretion as well as alpha-cell differentiation with both common and unique target genes
  • Hippo signaling may affect hepatocyte differentiation by influencing HNF4A and FOXA2 interactions with temporal enhancers
  • FOXA2 can be a regulator of NODAL expression
  • MEN1 is a novel protein partner of FOXA2, as a regulator of FOXA2, the biological functions of which extend beyond the pancreatic endocrine cells
  • SREBPF1 is part of a cluster of proneural transcription factors in radial glia and as a regulator of transcription factors controlling midbrain dopaminergic (mDA) neurogenesis, such as FOXA2
  • cell & other
    REGULATION
    induced by HNF6 in hepatoma cells
    Other activation of phosphatidylinositol3-kinase-akt by insulin induces Foxa2 phosphorylation, nuclear exclusion and inhibition of FOXA2-dependent transcriptional activity
    its expression and biological functions are regulated by various factors, including, in particular, insulin and glucagon
    unexpected role for DNA methylation in the activation of FOXA2 gene expression during differentiation
    sumoylation regulates FOXA2 protein expression and activity
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral somatic mutation      
    frequently mutated in endometrioid endometrial cancers (EEC)
    constitutional   deletion    
    heterozygous deletion of FOXA2 in a family with heterotaxy, panhypopituitarism, and biliary atresia, associated with decreased expression of NODAL
    Susceptibility to sporadic cas of maturity-onset diabetes of the young
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • mutant-/-have right expression of LEFTY2, (not NODAL), lack foregut and midgul endoderm and show anomalies of left-right (L/R) asymetry
  • chronic hyperinsulinemia in insulin-resitant syndromes in mice results in the cytoplasmic localization and inactivation of Foxa2, promoting lipid accumulation and insulin resistance in the liver
  • Foxa2 was overexpressed in islets from alpha-cell-specific Men1 mutant mice