Affinage

FOXA2

Hepatocyte nuclear factor 3-beta · UniProt Q9Y261

Length
457 aa
Mass
48.3 kDa
Annotated
2026-04-28
100 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FOXA2 is a forkhead/winged-helix pioneer transcription factor that opens chromatin at epigenetically primed sites in cooperation with lineage-specific co-factors and chromatin remodelers to orchestrate gene expression programs governing endoderm specification, hepatic lipid and glucose metabolism, pancreatic β-cell maturation, dopaminergic neuron identity, lung epithelial differentiation, and endometrial epithelial homeostasis. Its DNA-binding domain contacts DNA through helix H3 and wing 1, with wing 2 contributing to optimal affinity (PMID:28644006); chromatin opening requires synergistic co-binding with other transcription factors and is facilitated by SWI/SNF and INO80 remodelers acting with the histone variant H2A.Z, while DNA methylation opposes nucleosome depletion (PMID:23260146, PMID:31350899). FOXA2 activity is regulated by a convergence of post-translational modifications: insulin-PI3K-Akt phosphorylation at Thr156 drives nuclear exclusion and inactivation (PMID:15616563), glucagon/p300-mediated acetylation at Lys259 activates it while SIRT1 deacetylation destabilizes the protein (PMID:23416070, PMID:24875183), IKKα phosphorylation at S107/S111 suppresses transactivation (PMID:22196886), and E3 ligases TRIM36 and Smurf1 target FOXA2 for ubiquitin-dependent proteasomal degradation (PMID:37875418, PMID:31891682). In the nucleus, FOXA2 forms activating complexes with diverse co-regulators—including PGC-1β for hepatic β-oxidation (PMID:16459311), Nurr1 for dopaminergic gene derepression (PMID:24496614), Insm1/Neurod1 for β-cell maturation (PMID:25828096), Lhx1/Otx2/Ldb1 for anterior mesendoderm patterning (PMID:26494787), and nuclear receptors FXR/LXRα for ligand-dependent hepatic gene regulation (PMID:34246806)—and enables chromatin access for steroid hormone receptors ERα and AR during hepatocarcinogenesis (PMID:22265403).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2003 Medium

    Establishing that FOXA2 has transcriptional roles beyond endoderm development, this work showed FOXA2 inhibits adipocyte differentiation by activating Pref-1 and induces metabolic gene expression in mature adipocytes, broadening its known function to metabolic regulation in non-hepatic tissues.

    Evidence Gain-of-function in preadipocytes/adipocytes and Foxa2+/- haploinsufficient mice

    PMID:12865419

    Open questions at the time
    • Direct promoter binding to Pref-1 not shown by ChIP
    • Single-lab finding without independent replication
  2. 2004 High

    The first mechanistic explanation for how feeding/fasting cycles control FOXA2: insulin-PI3K-Akt phosphorylation at Thr156 drives FOXA2 nuclear exclusion, inactivating its lipid metabolism and ketogenesis transcriptional program—a constitutively nuclear T156A mutant bypasses this regulation.

    Evidence Adenoviral FOXA2-T156A in mouse liver, nuclear/cytoplasmic fractionation, gene expression

    PMID:15616563

    Open questions at the time
    • Identity of the phosphatase(s) that reverse Thr156 phosphorylation unknown
    • Whether additional kinases phosphorylate Thr156 in non-hepatic tissues not addressed
  3. 2006 High

    Identification of PGC-1β as a specific FOXA2 coactivator for hepatic lipid homeostasis established that FOXA2 does not act alone but requires coactivators to drive β-oxidation genes and VLDL secretion—processes inhibited by insulin through FOXA2.

    Evidence Adenoviral co-expression in ob/ob mouse liver with gene profiling and biochemical assays

    PMID:16459311

    Open questions at the time
    • Whether PGC-1β interaction is direct or bridged by other factors not resolved
    • Structural basis of FOXA2–PGC-1β interaction unknown
  4. 2007 High

    Conditional deletion in adult β-cells revealed FOXA2 governs insulin granule docking, first-phase secretion, and Ca²⁺/cAMP dynamics, establishing its role as a master regulator of β-cell secretory function beyond developmental specification.

    Evidence Inducible Foxa2 ablation in Foxa2(loxP/loxP);Pdx1-CreERT2 mice with electrophysiology

    PMID:17908556

    Open questions at the time
    • Direct target genes mediating granule docking not fully identified
    • Whether FOXA2 acts through the same targets in human β-cells not tested
  5. 2009 High

    Extension of the insulin–FOXA2 nuclear exclusion mechanism to the brain showed FOXA2 directly binds MCH and orexin promoters in hypothalamic neurons to control feeding and energy expenditure, establishing FOXA2 as a systemic metabolic integrator beyond liver.

    Evidence ChIP in hypothalamic neurons, brain-specific FOXA2-T156A transgenic mice, metabolic phenotyping

    PMID:19956259

    Open questions at the time
    • Whether other neuropeptide promoters are direct FOXA2 targets unknown
    • Cell-type specificity of FOXA2 targets across neuronal subtypes not mapped
  6. 2009 High

    Demonstrating FOXA2's pioneer function enables other transcription factors to access chromatin: combined Foxa1/2 deletion after liver specification abolished glucocorticoid receptor occupancy at the IL-6 promoter, causing cholangiocyte hyperplasia.

    Evidence Conditional Foxa1/2 double KO in postnatal liver, ChIP for GR occupancy

    PMID:19436110

    Open questions at the time
    • Relative individual contributions of Foxa1 versus Foxa2 not separated
    • Genome-wide scope of GR dependence on Foxa factors not determined
  7. 2010 High

    Live imaging revealed FOXA2 controls not only cell fate specification but also epithelial polarity: Foxa2-positive epiblast cells undergo EMT to form endoderm and then re-establish apical-basal polarity, which fails in Foxa2 mutants.

    Evidence Time-lapse confocal imaging and conditional mutagenesis in mouse embryos

    PMID:19234065

    Open questions at the time
    • Direct transcriptional targets mediating polarity re-establishment not identified
    • Whether FOXA2 controls polarity in adult epithelia not addressed
  8. 2011 High

    IKKα was identified as a second kinase controlling FOXA2: phosphorylation at S107/S111 suppresses transactivation rather than localization, linking TNFα inflammation to FOXA2 inactivation and downstream Notch pathway activation through reduced NUMB expression.

    Evidence Kinase assay, phosphosite mapping, gene expression, in vivo tumor models

    PMID:22196886

    Open questions at the time
    • Whether S107/S111 and Thr156 phosphorylation are coordinated or independent unknown
    • Phosphatase(s) reversing IKKα-mediated phosphorylation not identified
  9. 2012 High

    Genome-wide nucleosome mapping during ES-to-endoderm differentiation revealed the mechanism of FOXA2 pioneer activity: cooperation with H2A.Z and Nap1l1-coupled SWI/SNF/INO80 remodelers to deplete nucleosomes, opposed by DNA methylation.

    Evidence MNase-seq, ChIP-seq, loss-of-function in differentiating ESCs

    PMID:23260146

    Open questions at the time
    • Whether FOXA2 directly recruits SWI/SNF or INO80 versus acting in parallel unknown
    • Relative contributions of individual remodeling complexes not dissected
  10. 2012 High

    Conditional Foxa1/2 double deletion in liver revealed that FOXA factors enable sex hormone receptors (ERα, AR) to access chromatin, explaining sexually dimorphic hepatocarcinogenesis and establishing the paradigm that FOXA2 pioneers for steroid receptors.

    Evidence Conditional double-KO mice, ChIP, diethylnitrosamine-induced HCC

    PMID:22265403

    Open questions at the time
    • Whether FOXA2 alone suffices or Foxa1 is required remains unresolved due to double-KO design
    • Mechanism of FOXA-mediated sex hormone receptor recruitment not structurally defined
  11. 2013 High

    The acetylation–deacetylation switch was defined: glucagon/p300 acetylates FOXA2 at K259 to activate it, while SIRT1 deacetylates K259 to promote proteasomal degradation, providing a second major post-translational axis (distinct from Thr156 phosphorylation) for fasting–feeding regulation.

    Evidence In vitro acetylation assays, K259Q/K259R mutagenesis, adenoviral expression in mouse liver; LC-MS/MS, Co-IP, promoter reporters

    PMID:23416070 PMID:24875183

    Open questions at the time
    • Whether acetylation and phosphorylation at Thr156 are mutually exclusive or cooperative not tested
    • Identity of the ubiquitin ligase targeting deacetylated FOXA2 unknown
  12. 2013 Medium

    Hippo pathway kinases Mst1/2 were shown to stabilize and phosphorylate FOXA2, linking a developmental signaling cascade to FOXA2 protein levels in lung: loss of Mst1/2 impairs type II pneumocyte differentiation through reduced FOXA2 rather than YAP hyperactivity.

    Evidence Conditional KO, immunoprecipitation, phosphorylation assays in lung

    PMID:23620511

    Open questions at the time
    • Mst1/2 phosphorylation sites on FOXA2 not mapped
    • Single-lab finding; independent confirmation needed
  13. 2014 High

    In dopaminergic neuron specification, FOXA2 was shown to act as a co-activator by displacing the Nurr1–CoREST repressor complex: competitive formation of a Nurr1–FOXA2 activator complex reduces HDAC1 recruitment and increases histone acetylation at DA gene promoters.

    Evidence Reciprocal Co-IP, ChIP, histone acetylation assays, reporter assays in mDA differentiation

    PMID:24496614

    Open questions at the time
    • Direct structural interface between Nurr1 and FOXA2 not resolved
    • Whether FOXA2 opens chromatin prior to Nurr1 binding or only acts post-recruitment not distinguished
  14. 2015 High

    Discovery that Insm1, Neurod1, and FOXA2 form a trimeric complex on β-cell chromatin explained how combinatorial transcription factor binding—not individual factors—controls the mature β-cell gene expression program.

    Evidence Co-IP, ChIP-seq, Insm1 conditional ablation in adult β-cells

    PMID:25828096

    Open questions at the time
    • Stoichiometry and assembly order of the trimeric complex unknown
    • Whether this complex operates in human β-cells not confirmed
  15. 2015 High

    Identification of a FOXA2–Lhx1–Otx2–Ldb1 complex defined how FOXA2 participates in chromatin looping during anterior mesendoderm and midline development, extending its role from linear promoter activation to three-dimensional genome organization.

    Evidence Proteomics, ChIP-seq, conditional inactivation in mouse embryos

    PMID:26494787

    Open questions at the time
    • Whether Ldb1-mediated looping is FOXA2-dependent or Lhx1-dependent not resolved
    • Genome-wide loop structures organized by this complex not mapped
  16. 2017 High

    The 2.8 Å crystal structure of the FOXA2 forkhead domain bound to DNA provided the first atomic-resolution view of how helix H3 and wing 1 mediate DNA recognition, while ITC demonstrated wing 2 is required for full binding affinity.

    Evidence X-ray crystallography, isothermal titration calorimetry

    PMID:28644006

    Open questions at the time
    • Structure of full-length FOXA2 or FOXA2 in complex with nucleosomal DNA not available
    • How post-translational modifications alter the DNA-binding interface not structurally addressed
  17. 2019 High

    Genome-wide chromatin accessibility studies refined the pioneer factor model: FOXA2 selects binding sites at epigenetically primed chromatin but is insufficient alone to open chromatin—synergistic co-binding with other endoderm TFs is required for accessibility changes.

    Evidence ATAC-seq, ChIP-seq, ectopic FOXA2 in ESCs and endoderm differentiation

    PMID:31350899

    Open questions at the time
    • Identity of all required co-factors for chromatin opening not catalogued
    • Mechanism by which epigenetic priming licenses future FOXA2 binding unknown
  18. 2019 Medium

    SND1 was shown to promote FOXA2 ubiquitination via the E3 ligase Smurf1, providing the first identified ubiquitin ligase for FOXA2 degradation and linking FOXA2 loss to EMT and metastasis.

    Evidence Co-IP, ubiquitination assay, knockdown, in vivo xenograft in cervical cancer cells

    PMID:31891682

    Open questions at the time
    • Specific ubiquitination sites on FOXA2 not mapped
    • Single-lab finding in one cancer type
  19. 2021 High

    Multiple new regulatory inputs were identified: O-GlcNAcylation by OGT promotes ubiquitin-dependent FOXA2 degradation without affecting localization; FOXA2 is required for ligand-dependent chromatin access of nuclear receptors FXR and LXRα; and FOXP2 physically interacts with FOXA2 to activate E-cadherin.

    Evidence Co-IP, mass spectrometry, ATAC-seq/ChIP-seq in conditional mutant mice, immunofluorescence

    PMID:33718155 PMID:33843053 PMID:34246806

    Open questions at the time
    • O-GlcNAcylation sites on FOXA2 not fully mapped
    • Whether FOXP2–FOXA2 interaction occurs outside breast cancer contexts unknown
  20. 2022 High

    TET1 was identified as a physical interactor of FOXA2 whose DNA demethylase activity is required for FOXA2 binding at pancreatic progenitor loci, integrating epigenetic erasure with pioneer factor access.

    Evidence Co-IP, FOXA2 ChIP-seq in TET-KO hESCs, whole-genome bisulfite sequencing

    PMID:35798741

    Open questions at the time
    • Whether TET1 is recruited by FOXA2 or independently pre-marks sites not resolved
    • Applicability to non-pancreatic lineages not tested
  21. 2022 High

    FOXA2 was established as a key regulator of endometrial epithelial identity: conditional deletion combined with Pten loss causes lethal endometrial cancer with complete penetrance, and FOXA2 broadly modifies enhancer activity in endometrial epithelium.

    Evidence Conditional KO mouse models, RNA-seq, FOXA2 ChIP-seq, organoids

    PMID:35703180

    Open questions at the time
    • Direct FOXA2 targets mediating the tumor-suppressive function not fully enumerated
    • Whether FOXA2 loss alone (without Pten) initiates endometrial pathology unclear
  22. 2023 Medium

    TRIM36 was identified as a second E3 ligase that directly K48-polyubiquitinates FOXA2 for degradation; loss of FOXA2 downstream weakens Nrf2/GPX4 ferroptosis defense, linking FOXA2 protein stability to ferroptosis susceptibility.

    Evidence Co-IP, in vitro ubiquitination assay, knockdown, reporter assays in CRC cells

    PMID:37875418

    Open questions at the time
    • Specific lysine residues ubiquitinated by TRIM36 not identified
    • Single-lab finding; independent confirmation needed
  23. 2024 Medium

    In AR-independent prostate cancer, FOXA2 binds distinct developmental enhancers in an LSD1-dependent manner and collaborates with JUN/AP-1, revealing context-dependent enhancer selection underlying lineage plasticity in cancer.

    Evidence ChIP-seq, ATAC-seq, Co-IP, LSD1 inhibitor experiments, single-cell multiomics

    PMID:38851846

    Open questions at the time
    • Whether FOXA2 is sufficient or necessary for lineage plasticity transition not fully resolved
    • Single-lab finding in prostate cancer; generalizability to other cancers unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structure of full-length FOXA2 on nucleosomal DNA, how multiple post-translational modifications (phosphorylation, acetylation, O-GlcNAcylation, ubiquitination) are integrated in a single cell, and what determines FOXA2's tissue-specific enhancer selection and co-factor choice.
  • No full-length or nucleosome-bound FOXA2 structure available
  • Crosstalk among Thr156, K259, S107/S111, O-GlcNAc modifications not studied
  • Determinants of tissue-specific co-factor selection unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 1
Pathway
R-HSA-74160 Gene expression (Transcription) 8 R-HSA-1266738 Developmental Biology 3 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-4839726 Chromatin organization 3
Partners
INSM1LDB1LHX1NURR1PGC1BSIRT1SMURF1TET1
Complex memberships
Insm1-Neurod1-Foxa2Lhx1-Otx2-Foxa2-Ldb1Nurr1-Foxa2

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Insulin signaling causes nuclear exclusion of FOXA2, inactivating its transcriptional program of lipid metabolism and ketogenesis in hepatocytes; a phosphorylation-resistant mutant FOXA2-T156A remains constitutively nuclear and active, demonstrating that insulin-PI3K-Akt-mediated phosphorylation at Thr156 drives cytoplasmic localization and inactivation. Adenoviral expression of constitutively active FOXA2-T156A in mouse liver, nuclear exclusion assays, gene expression analysis Nature High 15616563
2006 FOXA2 is coactivated by PGC-1β (Pgc-1beta) to regulate hepatic lipid homeostasis; the FOXA2/Pgc-1beta complex activates genes of mitochondrial β-oxidation and induces microsomal transfer protein expression to increase apoB-containing VLDL secretion, a process inhibited by insulin through a FOXA2-dependent mechanism. Adenoviral co-expression of Foxa2 and Pgc-1beta in ob/ob mouse liver, gene expression profiling, biochemical assays Cell metabolism High 16459311
2007 Foxa2 inactivation in mature beta cells increases the pool of docked insulin granules and first-phase glucose-stimulated insulin secretion, while altering intracellular Ca2+ oscillations and cAMP production; Foxa2 regulates expression of genes involved in vesicular trafficking, membrane targeting, and fuel-secretion coupling. Inducible gene ablation in Foxa2(loxP/loxP);Pdx1-CreERT2 adult mice, electrophysiology, gene expression analysis Cell metabolism High 17908556
2009 Foxa2 in lateral hypothalamic neurons directly binds to MCH and orexin promoters during fasting to stimulate their expression; insulin signaling leads to nuclear exclusion of Foxa2 and reduced MCH/orexin expression; constitutive nuclear Foxa2 (T156A) in brain neurons increases food consumption, metabolism and insulin sensitivity. ChIP (promoter binding), conditional brain-specific Foxa2-T156A expression, behavioral and metabolic phenotyping Nature High 19956259
2013 Glucagon stimulation induces acetylation of FOXA2 at Lys259 via the coactivator p300; SIRT1 deacetylates FOXA2 at this residue; acetylation-mimicking mutation K259Q promotes FOXA2 activity and augments fatty acid oxidation and ketogenesis gene expression, while K259R is inhibitory. In vitro acetylation assays, acetylation-mimicking/deficient mutagenesis, adenoviral expression in mouse liver, gene expression analysis Cell metabolism High 23416070
2014 SIRT1 interacts with and deacetylates FOXA2; deacetylation by SIRT1 targets FOXA2 for proteasomal degradation and inhibits transcription from FOXA2-driven promoters (G6pase, CPT1a); upon nutrient withdrawal, the FOXA2-SIRT1 interaction is reduced, protecting FOXA2 from degradation by enhanced acetylation. LC-MS/MS identification of acetylated residues, Co-IP, in vitro deacetylation, promoter reporter assays PloS one High 24875183
2012 Foxa2 and the histone variant H2A.Z cooperate to mediate nucleosome depletion at target loci during ES cell differentiation into endoderm; nucleosome depletion is dependent on Nap1l1-coupled SWI/SNF and INO80 chromatin remodeling complexes; DNA methylation opposes nucleosome depletion. Genome-wide nucleosome mapping, ChIP-seq, loss-of-function experiments during ES cell differentiation Cell High 23260146
2011 IKKα phosphorylates FOXA2 at S107/S111, suppressing its transactivation activity and leading to decreased NUMB expression, which activates the NOTCH pathway and promotes cell proliferation and tumorigenesis; this defines a TNFα/IKKα/FOXA2/NUMB/NOTCH1 pathway. Co-IP, kinase assay, phosphorylation-site mapping, gene expression analysis, in vivo tumor models Molecular cell High 22196886
2017 Crystal structure (2.8 Å) of the FOXA2 DNA-binding domain (winged-helix fold) bound to a forkhead consensus site (GTAAACA) shows that helix H3 and wing 1 mediate DNA recognition; ITC assays demonstrate that wing 2 is required for optimal DNA binding. X-ray crystallography, isothermal titration calorimetry (ITC), structure-function analysis Biochemistry High 28644006
2014 Foxa2 acts as a co-activator that displaces the Nurr1-CoREST repressor complex; in the presence of Foxa2, the Nurr1-CoREST interaction is diminished through competitive formation of a Nurr1-Foxa2 activator complex, leading to reduced HDAC1 recruitment to DA gene promoters and increased histone H3 acetylation at these loci. Co-IP, ChIP, histone acetylation assays, promoter reporter assays in midbrain dopaminergic neuron differentiation Development (Cambridge, England) High 24496614
2019 Foxa2 binding site selection is directed by epigenetically primed chromatin (low-level active modifications in ESCs); Foxa2 binding alone is not sufficient for chromatin opening—increased chromatin accessibility requires synergistic co-binding with other endoderm transcription factors. ATAC-seq, ChIP-seq, ectopic expression of Foxa2 in ESCs, endoderm differentiation assays Nucleic acids research High 31350899
2015 Insm1, Neurod1, and Foxa2 physically interact and together bind regulatory sequences in mature pancreatic β-cells; combinatorial binding of all three factors, not Insm1 alone, explains a significant fraction of gene expression changes controlling β-cell maturity. Co-IP (direct protein-protein interaction), ChIP-seq, Insm1 conditional ablation in adult β-cells The EMBO journal High 25828096
2015 DEANR1 lncRNA facilitates SMAD2/3 recruitment to the FOXA2 promoter to activate FOXA2 expression during human endoderm differentiation; FOXA2 overexpression rescues endoderm differentiation defects caused by DEANR1 depletion. RNA interference, ChIP, rescue experiments with FOXA2 overexpression Cell reports Medium 25843708
2009 After liver specification, deletion of both Foxa1/2 causes IL-6 overexpression and cholangiocyte hyperplasia; the glucocorticoid receptor normally binds the IL-6 promoter to repress it, but fails to do so in Foxa1/2-deficient liver, establishing Foxa1/2 as required for glucocorticoid receptor occupancy at the IL-6 promoter. Conditional gene ablation, ChIP, gene expression analysis The Journal of clinical investigation High 19436110
2010 Foxa2 specifies endoderm cell fate and promotes epithelial polarity; Foxa2-positive epiblast cells undergo EMT to form endoderm, then re-acquire apical-basal polarity; Foxa2 mutant endodermal cells fail to maintain polarity and cannot establish proper cellular junctions. Time-lapse confocal imaging, immunohistochemistry, conditional mutagenesis in mouse embryos Development (Cambridge, England) High 19234065
2015 Lhx1, Otx2, and Foxa2 form a protein complex together with the chromatin-looping protein Ldb1; this complex cooperatively regulates anterior mesendoderm, node, and midline development. Co-IP/proteomics, ChIP-seq, conditional inactivation Genes & development High 26494787
2013 Neurogenin3 autoregulates its own expression by binding its gene promoter; Foxa2 synergistically cooperates with Neurogenin3 to amplify this autoregulation; inhibition of Foxa2 by RNA interference reduces Neurogenin3 autoactivation and attenuates the Neurogenin3-dependent endocrine developmental program. ChIP, reporter assays, RNAi, chromatin mark analysis The Journal of biological chemistry Medium 23471965
2009 Foxa2 binds to regulatory regions of the Gli2 gene and represses its expression at the transcriptional level, thereby attenuating Shh signaling and contributing to specification of ventral midbrain progenitor identity. ChIP, loss- and gain-of-function studies in mice Mechanisms of development Medium 21093585
2013 Hippo kinases Mst1/2 stabilize and phosphorylate Foxa2, which regulates pneumocyte maturation and surfactant protein expression; loss of Mst1/2 causes defects in type II pneumocyte differentiation independently of YAP hyperactivity but through impaired Foxa2. Conditional KO, immunoprecipitation, phosphorylation assays Proceedings of the National Academy of Sciences of the United States of America Medium 23620511
2018 FOXA2 physically interacts with FXR in a ligand-dependent manner; in the context of fasting/glucagon, FOXA2 inhibits FXR's ability to induce the anti-gluconeogenic SHP gene, while FXR/PKA phosphorylation activates a distinct subset of gluconeogenic genes; the interaction was identified by in vitro protein-protein interaction assays and cistromic approaches. In vitro protein-protein interaction assays, ChIP-seq (cistromics), site-directed mutagenesis, transactivation assays Journal of hepatology Medium 29981427
2021 Foxa2 is O-GlcNAcylated by OGT; O-GlcNAcylation activates ubiquitination-dependent degradation of FOXA2 and attenuates FOXA2-mediated transcription (including E-cadherin) without affecting nuclear localization, thereby promoting HCC cell migration. Co-IP, mass spectrometry, ubiquitination assays, reporter assays Journal of cellular physiology Medium 33843053
2021 FOXA2 represses the RIPK3 gene by binding its promoter; HDAC7 suppresses Foxa2 transcription; the circRNA CNEACR sequesters HDAC7 in the cytoplasm, preventing HDAC7 nuclear entry and thereby enabling FOXA2 expression and RIPK3 repression to inhibit necroptosis in cardiomyocytes. ChIP, co-IP, HDAC7 overexpression/knockdown, circRNA functional assays in H/R model Cell death and differentiation Medium 34588633
2021 Foxa2 is required for chromatin accessibility and ligand-dependent binding of type II nuclear receptors FXR and LXRα; co-immunoprecipitation shows Foxa2 interacts with FXR or LXRα in a ligand-dependent manner, suggesting they form an interdependent complex on DNA during ligand activation. ATAC-seq, ChIP-seq, co-immunoprecipitation, RNA-seq in Foxa2 conditional mutant mice Molecular metabolism High 34246806
2022 TET1 physically interacts with FOXA2 in endodermal lineage intermediates; TET1-dependent DNA demethylation is required for FOXA2 binding at pancreatic progenitor chromatin, and TET depletion leads to changes in FOXA2 binding at loci with low active chromatin modifications. Co-IP, genome-wide FOXA2 ChIP-seq in TET-KO hESCs, whole-genome bisulfite sequencing Nature communications High 35798741
2024 FOXA2 binds distinct developmental enhancers in AR-independent prostate cancer subtypes in an LSD1-dependent manner; FOXA2 collaborates with JUN/AP-1 at chromatin to promote transcriptional reprogramming enabling cancer cell lineage plasticity. ChIP-seq, ATAC-seq, Co-IP of FOXA2 with JUN, LSD1 inhibitor experiments, single-cell multiomics Nature communications Medium 38851846
2008 Foxa1 and Foxa2 directly bind to the Muc2 promoter (shown by ChIP and EMSA) and activate its transcription; mutation of three Foxa cis-elements inhibits Muc2 transactivation. ChIP, EMSA (gel shift), co-transfection reporter assays, siRNA knockdown Biochemical and biophysical research communications Medium 18336786
2003 Foxa2 inhibits adipocyte differentiation by activating transcription of the preadipocyte factor Pref-1 gene; in differentiated adipocytes, Foxa2 induces genes of glucose and fat metabolism including Glut4, hexokinase-2, hormone-sensitive lipase, and uncoupling proteins. Gain-of-function expression in preadipocytes and adipocytes, gene expression analysis, Foxa2+/- haploinsufficient mice The Journal of clinical investigation Medium 12865419
2012 Foxa1 and Foxa2 function as pioneer factors enabling coregulation of target genes by estrogen receptor (ERα) or androgen receptor (AR) during hepatocarcinogenesis; in Foxa1/2-deficient mice, this coregulation is lost and sexually dimorphic HCC is completely reversed. Conditional double-KO in mice, ChIP, gene expression analysis, diethylnitrosamine-induced HCC model Cell High 22265403
2020 PHF8 histone demethylase transcriptionally upregulates FOXA2 by demethylating repressive histone marks on the FOXA2 gene promoter; upregulated FOXA2 subsequently regulates gene expression programs driving neuroendocrine prostate cancer development. ChIP, TRAMP mouse model with Phf8 knockout, gene expression profiling The Journal of pathology Medium 33009820
2022 FOXA2 controls endometrial epithelial gene expression programs regulating cell proliferation, adhesion, and epithelial identity; simultaneous inactivation of both Foxa2 and Pten in endometrial epithelium leads to lethal endometrial cancers with complete penetrance, revealing synergism between FOXA2 and PI3K signaling; FOXA2 regulates gene expression broadly through modification of enhancer activity. Conditional KO mouse models, transcriptome sequencing, FOXA2 ChIP-seq (cistrome), organoid experiments The Journal of clinical investigation High 35703180
2014 FOXA2 induction by Hedgehog/SHH signaling in esophageal epithelium is direct; conditional activation of Shh in mouse esophageal epithelium induces FOXA2, while FOXA2 knockout embryos have reduced Foxa2 expression; FOXA2 in turn induces MUC2 and AGR2 expression to confer intestinal phenotype. Conditional Shh activation, Shh KO embryos, microarray, in vitro Hh pathway activation in cell lines The Journal of clinical investigation Medium 25083987
2015 FOXA2 directly regulates SCGB1A1 (club cell marker) expression; FOXA2 overexpression is sufficient to drive SCGB1A1 promoter activity and restore its expression in IL-13-treated or rhinovirus-infected cells; IL-4 and IL-13 repress both FOXA2 and SCGB1A1. Reporter assay, ChIP (implied by promoter-binding studies), overexpression rescue experiments American journal of respiratory cell and molecular biology Medium 30576223
2012 FOXA2 directly binds the FTO gene promoter and decreases FTO expression; HDAC3 maintains FTO/m6A/MYC signaling by repressing FOXA2 transcription; this regulatory axis is established by immunoprecipitation, dual-luciferase reporter assays, and ChIP. ChIP, dual-luciferase reporter assay, co-immunoprecipitation, siRNA knockdown Cancer gene therapy Medium 32655129
2021 FOXP2 interacts directly with FOXA2 (shown by Co-IP and immunofluorescence); this interaction is required for FOXP2's transcriptional activation of E-cadherin and PHF2, preventing EMT in breast cancer cells. Co-IP, immunofluorescence, ChIP (promoter binding), pulldown from FOXA2 with mass spectrometry Frontiers in oncology Medium 33718155
2009 GATA6 and FOXA2 directly bind to the Wnt6 promoter and cooperate to activate Wnt6 transcription, leading to activation of the canonical WNT-β-catenin pathway and induction of primitive extraembryonic endoderm differentiation. ChIP, reporter assay, overexpression studies in F9 teratocarcinoma cells Stem cells and development Medium 22607194
2019 SND1 promotes FOXA2 ubiquitination and degradation mediated by the E3 ligase Smurf1, thereby inhibiting FOXA2 expression and promoting EMT and metastasis in cervical cancer cells. Co-IP, ubiquitination assay, knockdown experiments, in vivo xenograft Experimental cell research Medium 31891682
2023 TRIM36 E3 ubiquitin ligase directly interacts with FOXA2 and induces K48-linked polyubiquitination, resulting in FOXA2 protein degradation; loss of FOXA2 weakens Nrf2/GPX4 pathway activation leading to ferroptosis in colorectal cancer cells. Co-IP, in vitro ubiquitination assay, FOXA2 knockdown, reporter assays Advanced science Medium 37875418
2012 Foxa2 regulates hepatic apoptosis through the cIAP1 signaling pathway; Foxa2 nuclear protein directly binds the cIAP1 promoter (shown by EMSA, gel supershift, and ChIP), and deletion of putative Foxa2 binding domains reduces cIAP1 promoter activity. EMSA, gel supershift, ChIP, promoter deletion reporter assays, siRNA/overexpression Cellular signalling Medium 23275033

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes. Nature 336 15616563
2012 Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. Cell 323 22265403
2007 Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner. Development (Cambridge, England) 232 17596284
2004 Foxa2 regulates alveolarization and goblet cell hyperplasia. Development (Cambridge, England) 226 14757645
2005 Compensatory roles of Foxa1 and Foxa2 during lung morphogenesis. The Journal of biological chemistry 224 15668254
2007 The foxa2 gene controls the birth and spontaneous degeneration of dopamine neurons in old age. PLoS biology 200 18076286
2004 Immunohistochemical localization of Foxa1 and Foxa2 in mouse embryos and adult tissues. Gene expression patterns : GEP 186 15567715
2010 Foxa2 is essential for mouse endometrial gland development and fertility. Biology of reproduction 183 20484741
2009 Foxa2 regulates polarity and epithelialization in the endoderm germ layer of the mouse embryo. Development (Cambridge, England) 167 19234065
2009 Wnt1-lmx1a forms a novel autoregulatory loop and controls midbrain dopaminergic differentiation synergistically with the SHH-FoxA2 pathway. Cell stem cell 167 19951692
2012 Foxa2 and H2A.Z mediate nucleosome depletion during embryonic stem cell differentiation. Cell 166 23260146
2017 Forkhead box a2 (FOXA2) is essential for uterine function and fertility. Proceedings of the National Academy of Sciences of the United States of America 141 28049832
2006 Coactivation of Foxa2 through Pgc-1beta promotes liver fatty acid oxidation and triglyceride/VLDL secretion. Cell metabolism 141 16459311
2022 FOXA2 drives lineage plasticity and KIT pathway activation in neuroendocrine prostate cancer. Cancer cell 124 36332622
2015 The lncRNA DEANR1 facilitates human endoderm differentiation by activating FOXA2 expression. Cell reports 121 25843708
2018 LncRNA-NEF antagonized epithelial to mesenchymal transition and cancer metastasis via cis-regulating FOXA2 and inactivating Wnt/β-catenin signaling. Oncogene 114 29311643
2009 Foxa1 and Foxa2 regulate bile duct development in mice. The Journal of clinical investigation 113 19436110
2003 Role of Foxa-2 in adipocyte metabolism and differentiation. The Journal of clinical investigation 113 12865419
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2013 Glucagon-induced acetylation of Foxa2 regulates hepatic lipid metabolism. Cell metabolism 92 23416070
2017 FOXA2 is a sensitive and specific marker for small cell neuroendocrine carcinoma of the prostate. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 89 28621319
2015 Lhx1 functions together with Otx2, Foxa2, and Ldb1 to govern anterior mesendoderm, node, and midline development. Genes & development 84 26494787
2018 miR-590-3p Promotes Ovarian Cancer Growth and Metastasis via a Novel FOXA2-Versican Pathway. Cancer research 80 29748371
2010 Integrative genomic analyses of CXCR4: transcriptional regulation of CXCR4 based on TGFbeta, Nodal, Activin signaling and POU5F1, FOXA2, FOXC2, FOXH1, SOX17, and GFI1 transcription factors. International journal of oncology 80 20043076
2014 Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett's metaplasia. The Journal of clinical investigation 77 25083987
2011 IKKα activation of NOTCH links tumorigenesis via FOXA2 suppression. Molecular cell 77 22196886
2015 Combined Nurr1 and Foxa2 roles in the therapy of Parkinson's disease. EMBO molecular medicine 76 25759364
2010 Foxa2 programs Th2 cell-mediated innate immunity in the developing lung. Journal of immunology (Baltimore, Md. : 1950) 76 20483781
2015 Insm1 cooperates with Neurod1 and Foxa2 to maintain mature pancreatic β-cell function. The EMBO journal 75 25828096
2022 Ginger nanoparticles mediated induction of Foxa2 prevents high-fat diet-induced insulin resistance. Theranostics 74 35154496
2007 Foxa2 controls vesicle docking and insulin secretion in mature Beta cells. Cell metabolism 74 17908556
2020 HDAC3-dependent transcriptional repression of FOXA2 regulates FTO/m6A/MYC signaling to contribute to the development of gastric cancer. Cancer gene therapy 72 32655129
2009 Distinct roles of FOXA2 and FOXA3 in allergic airway disease and asthma. American journal of respiratory and critical care medicine 72 19628779
2014 Transcription factors Foxa1 and Foxa2 are required for adult dopamine neurons maintenance. Frontiers in cellular neuroscience 70 25249938
2021 The circRNA CNEACR regulates necroptosis of cardiomyocytes through Foxa2 suppression. Cell death and differentiation 69 34588633
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2005 Monorail/Foxa2 regulates floorplate differentiation and specification of oligodendrocytes, serotonergic raphé neurones and cranial motoneurones. Development (Cambridge, England) 66 15677724
2018 FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer. eLife 65 30475207
2013 Hippo-Foxa2 signaling pathway plays a role in peripheral lung maturation and surfactant homeostasis. Proceedings of the National Academy of Sciences of the United States of America 64 23620511
2009 Regulation of adaptive behaviour during fasting by hypothalamic Foxa2. Nature 64 19956259
2017 Novel FOXA2 mutation causes Hyperinsulinism, Hypopituitarism with Craniofacial and Endoderm-derived organ abnormalities. Human molecular genetics 60 28973288
2023 FOXA2 Suppression by TRIM36 Exerts Anti-Tumor Role in Colorectal Cancer Via Inducing NRF2/GPX4-Regulated Ferroptosis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 58 37875418
2009 Molecular interactions between HNF4a, FOXA2 and GABP identified at regulatory DNA elements through ChIP-sequencing. Nucleic acids research 58 19822575
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2013 Foxa1 and Foxa2 are required for formation of the intervertebral discs. PloS one 54 23383217
2010 Foxa1 and Foxa2 positively and negatively regulate Shh signalling to specify ventral midbrain progenitor identity. Mechanisms of development 52 21093585
2020 Histone demethylase PHF8 drives neuroendocrine prostate cancer progression by epigenetically upregulating FOXA2. The Journal of pathology 51 33009820
2018 The nuclear bile acid receptor FXR is a PKA- and FOXA2-sensitive activator of fasting hepatic gluconeogenesis. Journal of hepatology 51 29981427
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2017 Direct conversion of human fibroblasts into hepatocyte-like cells by ATF5, PROX1, FOXA2, FOXA3, and HNF4A transduction. Scientific reports 48 29192290
2016 Transcriptomic and CRISPR/Cas9 technologies reveal FOXA2 as a tumor suppressor gene in pancreatic cancer. American journal of physiology. Gastrointestinal and liver physiology 48 27151939
2020 Selective inhibition of stemness through EGFR/FOXA2/SOX9 axis reduces pancreatic cancer metastasis. Oncogene 46 33288882
2008 Forkhead box transcription factors Foxa1 and Foxa2 are important regulators of Muc2 mucin expression in intestinal epithelial cells. Biochemical and biophysical research communications 46 18336786
2022 A FoxA2+ long-term stem cell population is necessary for growth plate cartilage regeneration after injury. Nature communications 45 35523895
2012 β-Catenin signaling regulates Foxa2 expression during endometrial hyperplasia formation. Oncogene 45 22945641
2019 The Club Cell Marker SCGB1A1 Downstream of FOXA2 is Reduced in Asthma. American journal of respiratory cell and molecular biology 42 30576223
2022 FoxA1 and FoxA2 control growth and cellular identity in NKX2-1-positive lung adenocarcinoma. Developmental cell 41 35835117
2014 Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation. Development (Cambridge, England) 41 24496614
2018 microRNA-141-3p fosters the growth, invasion, and tumorigenesis of cervical cancer cells by targeting FOXA2. Archives of biochemistry and biophysics 39 30222949
2017 Structure of the Forkhead Domain of FOXA2 Bound to a Complete DNA Consensus Site. Biochemistry 39 28644006
2018 Regulation of Cancer Stem Cell Self-Renewal by HOXB9 Antagonizes Endoplasmic Reticulum Stress-Induced Melanoma Cell Apoptosis via the miR-765-FOXA2 Axis. The Journal of investigative dermatology 38 29408459
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2012 Frequent downregulation of the transcription factor Foxa2 in lung cancer through epigenetic silencing. Lung cancer (Amsterdam, Netherlands) 38 22341411
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2015 Brachyury, Foxa2 and the cis-Regulatory Origins of the Notochord. PLoS genetics 36 26684323
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2020 Inactivation of FOXA2 by Respiratory Bacterial Pathogens and Dysregulation of Pulmonary Mucus Homeostasis. Frontiers in immunology 32 32269574
2008 Foxa2: the rise and fall of dopamine neurons. Cell stem cell 32 18371430
2018 Congenital Hyperinsulinism and Hypopituitarism Attributable to a Mutation in FOXA2. The Journal of clinical endocrinology and metabolism 30 29329447
2010 The Siah2-HIF-FoxA2 axis in prostate cancer – new markers and therapeutic opportunities. Oncotarget 30 21037926
2021 O-GlcNAcylation promotes the migratory ability of hepatocellular carcinoma cells via regulating FOXA2 stability and transcriptional activity. Journal of cellular physiology 29 33843053
2017 MicroRNA-200a inhibits cell growth and metastasis by targeting Foxa2 in hepatocellular carcinoma. Journal of Cancer 29 28367241
2012 A novel role for FOXA2 and SHH in organizing midbrain signaling centers. Developmental biology 29 22750257
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2021 FOXA2-Interacting FOXP2 Prevents Epithelial-Mesenchymal Transition of Breast Cancer Cells by Stimulating E-Cadherin and PHF2 Transcription. Frontiers in oncology 28 33718155
2020 Exendin-4 restores airway mucus homeostasis through the GLP1R-PKA-PPARγ-FOXA2-phosphatase signaling. Mucosal immunology 28 32034274
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2009 Foxa2-dependent hepatic gene regulatory networks depend on physiological state. Physiological genomics 27 19417011
2022 CD44 Promotes Breast Cancer Metastasis through AKT-Mediated Downregulation of Nuclear FOXA2. Biomedicines 26 36289750
2019 SND1 facilitates the invasion and migration of cervical cancer cells by Smurf1-mediated degradation of FOXA2. Experimental cell research 26 31891682
2017 Identification and characterization of a FOXA2-regulated transcriptional enhancer at a type 2 diabetes intronic locus that controls GCKR expression in liver cells. Genome medicine 26 28683826
2012 GATA6 and FOXA2 regulate Wnt6 expression during extraembryonic endoderm formation. Stem cells and development 26 22607194
2018 Curcumin Inhibits Growth of Human NCI-H292 Lung Squamous Cell Carcinoma Cells by Increasing FOXA2 Expression. Frontiers in pharmacology 25 29456509
2017 MicroRNA-187 promotes growth and metastasis of gastric cancer by inhibiting FOXA2. Oncology reports 25 28098868
2014 Arx together with FoxA2, regulates Shh floor plate expression. Developmental biology 25 24968361
2023 Gambogenic acid inhibits proliferation and ferroptosis by targeting the miR-1291/FOXA2 and AMPKα/SLC7A11/GPX4 axis in colorectal cancer. Cell biology international 24 37471707
2021 MRE11 promotes oral cancer progression through RUNX2/CXCR4/AKT/FOXA2 signaling in a nuclease-independent manner. Oncogene 24 33927349
2019 Transcriptional Regulation Factors of the Human Mitochondrial Aspartate/Glutamate Carrier Gene, Isoform 2 (SLC25A13): USF1 as Basal Factor and FOXA2 as Activator in Liver Cells. International journal of molecular sciences 24 30995827
2014 SIRT1 mediates FOXA2 breakdown by deacetylation in a nutrient-dependent manner. PloS one 24 24875183
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2011 Directed expression of Gata2, Mash1, and Foxa2 synergize to induce the serotonergic neuron phenotype during in vitro differentiation of embryonic stem cells. Stem cells (Dayton, Ohio) 24 21472823
2022 FOXA2 suppresses endometrial carcinogenesis and epithelial-mesenchymal transition by regulating enhancer activity. The Journal of clinical investigation 23 35703180
2012 Foxa2 may modulate hepatic apoptosis through the cIAP1 pathway. Cellular signalling 23 23275033
2019 Integrative analysis of the forkhead box A2 (FOXA2) cistrome for the human endometrium. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21 30951376
2019 MiR-942 regulates the function of breast cancer cell by targeting FOXA2. Bioscience reports 21 31701999
2022 TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation. Nature communications 20 35798741
2021 Pioneer factor Foxa2 enables ligand-dependent activation of type II nuclear receptors FXR and LXRα. Molecular metabolism 20 34246806
2019 Increase in secreted airway mucins and partial Muc5b STAT6/FoxA2 regulation during Pneumocystis primary infection. Scientific reports 20 30765827
2019 Opposing Roles of the Forkhead Box Factors FoxM1 and FoxA2 in Liver Cancer. Molecular cancer research : MCR 20 30814128