FOXA2

Summary

FOXA2 (forkhead box A2, HGNC:5022) is a protein-coding gene on chromosome 20p11.21, encoding Hepatocyte nuclear factor 3-beta (Q9Y261). Transcription factor that is involved in embryonic development, establishment of tissue-specific gene expression and regulation of gene expression in differentiated tissues.

This gene encodes a member of the forkhead class of DNA-binding proteins. These hepatocyte nuclear factors are transcriptional activators for liver-specific genes such as albumin and transthyretin, and they also interact with chromatin. Similar family members in mice have roles in the regulation of metabolism and in the differentiation of the pancreas and liver. This gene has been linked to sporadic cases of maturity-onset diabetes of the young. Transcript variants encoding different isoforms have been identified for this gene.

Source: NCBI Gene 3170 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyperinsulinism (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 17
• Clinical variants (ClinVar): 178 total — 2 likely-pathogenic
• Phenotypes (HPO): 39
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• Transcription factor: yes — 151 downstream targets (CollecTRI)
• MANE Select transcript: NM_021784

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5022
Approved symbol	FOXA2
Name	forkhead box A2
Location	20p11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000125798
Ensembl biotype	protein_coding
OMIM	600288
Entrez	3170

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000377115, ENST00000419308, ENST00000938926

RefSeq mRNA: 2 — MANE Select: NM_021784 NM_021784, NM_153675

CCDS: CCDS13147, CCDS46585

Canonical transcript exons

ENST00000419308 — 2 exons

Exon	Start	End
ENSE00001391596	22584192	22584572
ENSE00003907941	22580998	22583154

Expression profiles

Bgee: expression breadth ubiquitous, 105 present calls, max score 97.96.

FANTOM5 (CAGE): breadth broad, TPM avg 2.5566 / max 247.1904, expressed in 322 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186637	1.1073	241
186640	0.7853	227
186639	0.5593	188
186645	0.0897	39
186643	0.0151	9

Top tissues by expression

268 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	97.96	gold quality
pylorus	UBERON:0001166	94.14	gold quality
buccal mucosa cell	CL:0002336	93.74	gold quality
type B pancreatic cell	CL:0000169	90.44	silver quality
right uterine tube	UBERON:0001302	89.29	gold quality
right lobe of liver	UBERON:0001114	89.00	gold quality
olfactory bulb	UBERON:0002264	86.82	gold quality
cardia of stomach	UBERON:0001162	86.78	gold quality
liver	UBERON:0002107	86.56	gold quality
islet of Langerhans	UBERON:0000006	86.20	gold quality
body of pancreas	UBERON:0001150	85.86	gold quality
lower lobe of lung	UBERON:0008949	85.38	gold quality
pancreas	UBERON:0001264	85.31	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.14	gold quality
epithelial cell of pancreas	CL:0000083	83.48	silver quality
mucosa of sigmoid colon	UBERON:0004993	82.90	gold quality
colonic mucosa	UBERON:0000317	80.49	gold quality
mucosa of transverse colon	UBERON:0004991	79.76	gold quality
rectum	UBERON:0001052	79.68	gold quality
lung	UBERON:0002048	79.61	gold quality
diaphragm	UBERON:0001103	79.29	gold quality
upper lobe of lung	UBERON:0008948	78.62	gold quality
upper lobe of left lung	UBERON:0008952	78.12	gold quality
right lung	UBERON:0002167	77.84	gold quality
body of stomach	UBERON:0001161	77.52	gold quality
stomach	UBERON:0000945	77.24	gold quality
endometrium	UBERON:0001295	75.50	gold quality
tibia	UBERON:0000979	75.48	gold quality
visceral pleura	UBERON:0002401	75.06	gold quality
epithelium of bronchus	UBERON:0002031	73.76	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	16.56
E-MTAB-9388	yes	14.04

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

151 targets.

Target	Regulation
ABCA1	Repression
ABCA3	Activation
ABCB1	Activation
ABCC2
ABCC8	Activation
ADAM2
ADH1A
ADORA2B	Activation
AFP	Activation
AGR2	Unknown
AGXT
AHSG	Activation
ALAS2
ALB
ANO2	Activation
APOA1	Unknown
APOB
APOM	Activation
AQP3	Unknown
AQP9
ATIC
BAX	Activation
BIRC2	Activation
BIRC3
CA2
CADM1	Activation
CCN1	Unknown
CD320	Repression
CDH1	Activation
CDH17

JASPAR motifs

Motif	Name	Family
MA0047.3	FOXA2	FOX
MA0047.4	FOXA2	FOX

JASPAR matrix evidence (PMIDs): PMID:28644006

Upstream regulators (CollecTRI, top): CDX1, CEBPA, CTNNB1, E2F1, FERD3L, FOXA1, FOXA2, FOXD3, FOXH1, FOXM1, FOXO1, GLI1, GLI2, HNF4A, HOXB3, NANOG, NFKB1, ONECUT1, PDX1, POU5F1, SMAD3, SSRP1, USF1, ZGLP1

miRNA regulators (miRDB)

65 targeting FOXA2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-609	99.82	64.26	505
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-3618	99.69	68.57	1012
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-6752-5P	99.59	67.32	1243

Literature-anchored findings (GeneRIF, showing 40)

• Foxa2 regulates the expression of genes important for glucose sensing in pancreatic beta-cells. (PMID:11875061)
• differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNF3beta transcription factors (PMID:12124776)
• FOXA2 expression is regulated by HNF6 in human hepatoma cells (PMID:12509444)
• HNF4-alpha, HNF3-beta and Sp1/Sp3 are important in regulation of prothrombin expression (PMID:12911579)
• activation of phosphatidylinositol 3-kinase-Akt by insulin induces Foxa-2 phosphorylation, nuclear exclusion, and inhibition of Foxa-2-dependent transcriptional activity (PMID:14500912)
• HNF3beta represses transcription of the OATP8 but not the OATP-C gene, providing a mechanism for reduced expression of OATP8 in hepatocellular carcinoma (PMID:14739090)
• Hepatic nuclear factor 3 and nuclear factor 1 regulate 5-aminolevulinate synthase gene expression and are involved in insulin repression (PMID:15123725)
• Expression of HNF3 beta led to significant growth reduction, proliferation arrest, apoptosis, and loss of clonogenic ability, suggesting additionally that HNF3 beta is a novel tumor suppressor in lung cancer. (PMID:15205324)
• the HNF-3 site in the fibrinogen beta promoter is important for IL6-induced expression, and its activity is influenced by the adjacent -148C/T polymorphism (PMID:15737987)
• suggest that Foxa proteins are important in prostate carcinogenesis; in particular, Foxa2 may be involved in progression of prostate cancer to androgen independence (PMID:16001449)
• HESCs expressing FOXA2 gene were induced to differentiate via embryoid bodies. (PMID:16675598)
• These results define a critical role for Fox-1 and Fox-2 proteins in exon 4 inclusion of calcitonin/CGRP pre-mRNA and establish a regulatory network that controls the fate of exon 4. (PMID:17101796)
• HNF6 DNA binding is selectively abrogated through lack of post-translational modification and interaction with FOXA2. Targeting of FOXA2 and HNF6 may therefore enable mechanism-based therapy for colorectal liver metastases (PMID:17283222)
• results suggest that Foxa2 is one of the transcriptional regulators for AQP3 gene expression regulated by insulin (PMID:17471492)
• functional significance of an intronic splicing enhancer, UGCAUG, and its cognate splicing factor, mFox2A, on exon 16 splicing during erythroid differentiation (PMID:17715393)
• Foxa2 activity increases plasma high density lipoprotein levels by regulating apolipoprotein M (PMID:18381283)
• 15-PGDH is a direct downstream effector of HNF3beta . (PMID:18593902)
• Foxa2 has a role in Foxa2 bile acid homeostasis and endoplasmic reticulum stress (PMID:18660816)
• Tet-induced HNF3beta expression sensitizes bone marrow-derived mesenchymal stem cells to bFGF signals. (PMID:18666263)
• Quantitative reverse transcription-polymerase chain reaction (RT-PCR) showed decreased expression of HNF3 beta/FoxA2 and TTF-1 mRNA in papillary thyroid carcinoma cell lines, when compared with normal thyroid cells (PMID:18682709)
• Data suggest that a group of transcription factors, including MafA and Foxa2, regulate expression of two major autoantigens in type 1 diabetes, including islet-specific glucose-6-phosphatase catalytic subunit-related protein. (PMID:18753309)
• Genetic variants of FOXA2 are associated with type 2 diabetes. (PMID:18797817)
• Marker for a progenitor cell population which gives rise to the majority of cells in endoderm-derived organs. (PMID:18798232)
• These results suggest that HNF4alpha and HNF3beta likely participate in hepatitis B virus replication in hepatitis B patients, or that hepatitis B virus replication may somehow influence the expression of HNF4alpha and HNF3beta in the liver. (PMID:19302415)
• insulin inhibits nuclear export-independent inhibition of Foxa2 (PMID:19589781)
• Results indicate that another transcription factor, Foxa2, is at least partly responsible for the attenuating effect of TNFalpha on insulin action on PEPCK expression and glucose production in HepG2 cells. (PMID:19769745)
• our results reveal an EBP1-Foxa-AGR2 signaling circuit with functional significance in metastatic prostate cancer. (PMID:20048076)
• We show here that Foxa2, a forkhead transcription factor whose role in midbrain DA neuron development was recently revealed, synergistically cooperates with Nurr1 to induce a DA phenotype, midbrain-specific gene expression, and neuronal maturation. (PMID:20049900)
• identified the positive control element and provided the first evidence that FOXA2 is involved in up-regulation of SOX14 expression in HepG2 and U87MG cell lines (PMID:20074681)
• identified a low-frequency variant (rs1209523; minor allele frequency = 0.043) near FOXA2 that was associated with fasting glucose levels in European Americans (n = 7428, p value = 1.3 x 10(-5)) (PMID:20152958)
• In pancreatic cancer cell lines, FOXA1/2 expression is consistently suppressed in experimental EMT models and RNAi silencing of FOXA1/2 alone is sufficient to induce EMT. (PMID:20160041)
• HCV infection of human hepatocytes impaired insulin-induced FoxO1 translocation from the nucleus to the cytoplasm and reduced accumulation of FoxA2 in the nucleus. (PMID:20357092)
• these results indicate that ALR is regulated by Foxa2, and this regulation may be amplified by IL-6. (PMID:20382118)
• FOXA2 can bind to slug promoter through a conserved binding site, and that the DNA-binding region and transactivation region II of FOXA2 are required for repression of the slug promoter. (PMID:20820189)
• functional knockdown of FOXA2 recovered HNF6 activity and inhibited growth of tumor-cells and may possibly represent a novel therapeutic target in primary and secondary liver malignancies (PMID:20967225)
• Review: Define the regulatory axis consisting of Siah2 and HIF-1alpha/FoxA2 cooperation and suggest novel therapeutic modalities to treat these most aggressive forms of prostate cancer. (PMID:21037926)
• despite the conservation of the canonical binding motif, the great majority of binding regions for FOXA2 in human liver and for PPARgamma in human adipocytes are not in the orthologous locations corresponding to the mouse genome, and vice versa (PMID:21292830)
• these results collectively suggest that, in melanoma cells, Foxa2 expression is silenced and therefore elafin is maintained unexpressed to facilitate cell proliferation in the disease melanoma. (PMID:21466784)
• Short interfering RNA-mediated knockdown of FOXA1 decreased the expression of DIO1 mRNA, but knockdown of both FOXA1 and FOXA2 restored it. (PMID:22067325)
• pFOXA2 expression is positively correlated with IKKalpha and activated NOTCH1 expression in tumor tissues. (PMID:22196886)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxa2	ENSDARG00000003411
mus_musculus	Foxa2	ENSMUSG00000037025
rattus_norvegicus	Foxa2	ENSRNOG00000013133
drosophila_melanogaster	fkh	FBGN0000659
caenorhabditis_elegans		WBGENE00004013

Paralogs (41): FOXP3 (ENSG00000049768), FOXC1 (ENSG00000054598), FOXJ2 (ENSG00000065970), FOXF1 (ENSG00000103241), FOXN1 (ENSG00000109101), FOXM1 (ENSG00000111206), FOXP1 (ENSG00000114861), FOXO3 (ENSG00000118689), FOXA1 (ENSG00000129514), FOXJ1 (ENSG00000129654), FOXK2 (ENSG00000141568), FOXO1 (ENSG00000150907), FOXH1 (ENSG00000160973), FOXQ1 (ENSG00000164379), FOXK1 (ENSG00000164916), FOXD4 (ENSG00000170122), FOXA3 (ENSG00000170608), FOXB1 (ENSG00000171956), FOXR1 (ENSG00000176302), FOXL1 (ENSG00000176678), FOXC2 (ENSG00000176692), FOXE1 (ENSG00000178919), FOXS1 (ENSG00000179772), FOXL2 (ENSG00000183770), FOXO4 (ENSG00000184481), FOXD4L1 (ENSG00000184492), FOXD4L4 (ENSG00000184659), FOXD2 (ENSG00000186564), FOXI2 (ENSG00000186766), FOXE3 (ENSG00000186790), FOXD3 (ENSG00000187140), FOXD4L3 (ENSG00000187559), FOXR2 (ENSG00000189299), FOXJ3 (ENSG00000198815), FOXO6 (ENSG00000204060), FOXB2 (ENSG00000204612), FOXD4L5 (ENSG00000204779), FOXI3 (ENSG00000214336), FOXL3 (ENSG00000248767), FOXD1 (ENSG00000251493)

Protein

Protein identifiers

Hepatocyte nuclear factor 3-beta — Q9Y261 (reviewed: Q9Y261)

Alternative names: Forkhead box protein A2, Transcription factor 3B

All UniProt accessions (2): Q9Y261, B0ZTD4

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that is involved in embryonic development, establishment of tissue-specific gene expression and regulation of gene expression in differentiated tissues. Is thought to act as a ‘pioneer’ factor opening the compacted chromatin for other proteins through interactions with nucleosomal core histones and thereby replacing linker histones at target enhancer and/or promoter sites. Binds DNA with the consensus sequence 5’-[AC]A[AT]T[AG]TT[GT][AG][CT]T[CT]-3’. In embryonic development is required for notochord formation. Involved in the development of multiple endoderm-derived organ systems such as the liver, pancreas and lungs; FOXA1 and FOXA2 seem to have at least in part redundant roles. Originally described as a transcription activator for a number of liver genes such as AFP, albumin, tyrosine aminotransferase, PEPCK, etc. Interacts with the cis-acting regulatory regions of these genes. Involved in glucose homeostasis; regulates the expression of genes important for glucose sensing in pancreatic beta-cells and glucose homeostasis. Involved in regulation of fat metabolism. Binds to fibrinogen beta promoter and is involved in IL6-induced fibrinogen beta transcriptional activation.

Subunit / interactions. Binds DNA as a monomer. Binds TLE1. Interacts with FOXA1 and FOXA3. Interacts with PRKDC. Interacts with AKT1. Interacts with TET1; this interaction may recruit TET1 to specific genomic loci to mediate their demethylation.

Subcellular location. Nucleus. Cytoplasm.

Post-translational modifications. Phosphorylation on Thr-156 abolishes binding to target promoters and subsequent transcription activation upon insulin stimulation.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y261-1	1	yes
Q9Y261-2	2

RefSeq proteins (2): NP_068556, NP_710141 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001766	Fork_head_dom	Domain
IPR013638	Fork-head_N	Domain
IPR018122	TF_fork_head_CS_1	Conserved_site
IPR018533	Forkhead_box_C	Domain
IPR030456	TF_fork_head_CS_2	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR050211	FOX_domain-containing	Family

Pfam: PF00250, PF08430, PF09354

UniProt features (29 total): modified residue 10, helix 4, strand 4, region of interest 3, compositionally biased region 3, chain 1, DNA-binding region 1, splice variant 1, sequence variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7YZE	X-RAY DIFFRACTION	1.99
7YZF	X-RAY DIFFRACTION	2.18
5X07	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y261-F1	58.29	0.18

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (10): 212, 283, 301, 303, 306, 307, 309, 436, 457, 156

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-210745	Regulation of gene expression in beta cells
R-HSA-9764790	Positive Regulation of CDH1 Gene Transcription
R-HSA-9796292	Formation of axial mesoderm
R-HSA-9823730	Formation of definitive endoderm
R-HSA-9925561	Developmental Lineage of Pancreatic Acinar Cells
R-HSA-9925563	Developmental Lineage of Pancreatic Ductal Cells
R-HSA-9937080	Developmental Lineage of Multipotent Pancreatic Progenitor Cells

MSigDB gene sets: 378 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_AXIS_SPECIFICATION, HNF3ALPHA_Q6, GOBP_BEHAVIOR, GOBP_REGULATION_OF_WOUND_HEALING, PID_HNF3B_PATHWAY, GOBP_RESPONSE_TO_PEPTIDE, GOBP_REGULATION_OF_COAGULATION, GOBP_REGULATION_OF_CELL_CELL_ADHESION_MEDIATED_BY_CADHERIN, GOBP_ADULT_BEHAVIOR, GOBP_INSULIN_SECRETION, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, HALMOS_CEBPA_TARGETS_UP, GOBP_PRIMITIVE_STREAK_FORMATION, GOBP_REGULATION_OF_HORMONE_LEVELS

GO Biological Process (20): negative regulation of transcription by RNA polymerase II (GO:0000122), cell fate specification (GO:0001708), chromatin organization (GO:0006325), regulation of transcription by RNA polymerase II (GO:0006357), adult locomotory behavior (GO:0008344), anatomical structure morphogenesis (GO:0009653), negative regulation of epithelial to mesenchymal transition (GO:0010719), cell differentiation (GO:0030154), regulation of blood coagulation (GO:0030193), endocrine pancreas development (GO:0031018), positive regulation of embryonic development (GO:0040019), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0061178), response to interleukin-6 (GO:0070741), dopaminergic neuron differentiation (GO:0071542), primitive streak formation (GO:0090009), positive regulation of cell-cell adhesion mediated by cadherin (GO:2000049), positive regulation of gastrulation (GO:2000543), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (15): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), nucleic acid binding (GO:0003676), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), transcription corepressor activity (GO:0003714), protein domain specific binding (GO:0019904), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515), transcription factor binding (GO:0008134), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cell junction (GO:0030054)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Developmental Cell Lineages of the Exocrine Pancreas	3
Gastrulation	2
Regulation of beta-cell development	1
Regulation of CDH1 Gene Transcription	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
cellular anatomical structure	4
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
regulation of DNA-templated transcription	3
negative regulation of DNA-templated transcription	2
cellular developmental process	2
anatomical structure development	2
DNA-templated transcription	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
binding	2
protein binding	2
cell fate commitment	1
cellular component organization	1
locomotory behavior	1
adult behavior	1
developmental process	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
negative regulation of cell differentiation	1
negative regulation of multicellular organismal process	1
blood coagulation	1
regulation of response to external stimulus	1
regulation of coagulation	1
regulation of wound healing	1
regulation of hemostasis	1
pancreas development	1
endocrine system development	1
embryo development	1
regulation of embryonic development	1
positive regulation of developmental process	1
positive regulation of multicellular organismal process	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
insulin secretion involved in cellular response to glucose stimulus	1
regulation of insulin secretion	1
regulation of cellular localization	1
response to cytokine	1
neuron differentiation	1
gastrulation with mouth forming second	1

Protein interactions and networks

STRING

2754 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXA2	ONECUT1	Q9UBC0	948
FOXA2	SOX17	Q9H6I2	940
FOXA2	HNF1A	P20823	893
FOXA2	POU5F1	P31359	877
FOXA2	HIF1A	Q16665	874
FOXA2	PDX1	P52945	866
FOXA2	AR	P10275	857
FOXA2	TTR	P02766	855
FOXA2	NKX2-2	O95096	847
FOXA2	HNF4A	P41235	845
FOXA2	GATA4	P43694	845
FOXA2	GATA6	P78327	842
FOXA2	OTX2	P32243	837
FOXA2	SOX2	P48431	830
FOXA2	NKX6-1	P78426	827

IntAct

3 interactions, top by confidence:

A	B	Type	Score
FOXA2	TLE1	psi-mi:“MI:0915”(physical association)	0.370
FOXA2	FOXN2	psi-mi:“MI:0914”(association)	0.350
FOXA1	TBP	psi-mi:“MI:0403”(colocalization)	0.350

BioGRID (32): HOXD13 (Affinity Capture-MS), SATB2 (Affinity Capture-MS), ADAR (Affinity Capture-MS), AGL (Affinity Capture-MS), DACH1 (Affinity Capture-MS), FOXN2 (Affinity Capture-MS), HOXB13 (Affinity Capture-MS), NACC1 (Affinity Capture-MS), SALL1 (Affinity Capture-MS), FOXA2 (Two-hybrid), FOXA2 (Co-localization), FOXA2 (Affinity Capture-MS), FOXA2 (Reconstituted Complex), FOXA2 (Reconstituted Complex), FOXA2 (Reconstituted Complex)

ESM2 similar proteins: A2TED3, O00570, O57401, O95409, P06602, P07548, P09085, P14734, P16241, P20264, P22544, P23441, P23757, P31361, P32027, P32182, P32242, P35583, P39768, P40764, P41225, P43241, P43698, P43699, P48430, P48431, P48432, P50220, P53783, P53784, P54231, P54269, P56224, P80205, Q04649, Q07687, Q24255, Q24533, Q2PG84, Q2Z1R2

Diamond homologs: A0A1W2PRP0, A0A8V0YY16, A3KNJ3, A8MTJ6, B5RHS5, D3Z120, O00358, O35392, O43638, O60548, O88470, P32027, P32030, P35583, P55316, P56260, P58012, P79772, Q00939, Q02360, Q02361, Q12948, Q12950, Q12951, Q12952, Q13461, Q16676, Q18694, Q1A1A1, Q1A1A2, Q1A1A3, Q1A1A4, Q1A1A5, Q1A1A6, Q28D67, Q28HT3, Q32NP8, Q3I5G5, Q3SYB3, Q4VUF1

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
CHUK	down-regulates	FOXA2	phosphorylation
CTNNB1	“up-regulates quantity by expression”	FOXA2	“transcriptional regulation”
FOXA2	“down-regulates activity”	OTX2	binding
POU5F1	“down-regulates quantity by repression”	FOXA2	“transcriptional regulation”
NANOG	“down-regulates quantity by repression”	FOXA2	“transcriptional regulation”
AKT	“down-regulates activity”	FOXA2	phosphorylation
AKT	down-regulates	FOXA2	phosphorylation
FOXA2	“down-regulates quantity by repression”	SLCO1B3	“transcriptional regulation”
FOXA2	“up-regulates quantity by expression”	DLK1	“transcriptional regulation”
FOXA2	“up-regulates quantity by expression”	AHSG	“transcriptional regulation”

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — UCEC.

Clinical variants and AI predictions

ClinVar

178 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	111
Likely benign	36
Benign	14

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
2502182	NM_021784.5(FOXA2):c.506C>G (p.Ser169Trp)	Likely pathogenic
3544360	NM_021784.5(FOXA2):c.619C>T (p.Gln207Ter)	Likely pathogenic

SpliceAI

490 predictions. Top by Δscore:

Variant	Effect	Δscore
20:22583150:TAGCC:T	acceptor_gain	1.0000
20:22583151:AGCC:A	acceptor_gain	1.0000
20:22583151:AGCCC:A	acceptor_loss	1.0000
20:22583153:CC:C	acceptor_gain	1.0000
20:22583154:CC:C	acceptor_gain	1.0000
20:22583155:C:CA	acceptor_loss	1.0000
20:22583156:T:C	acceptor_loss	1.0000
20:22583170:C:T	acceptor_gain	1.0000
20:22583171:G:T	acceptor_gain	1.0000
20:22584186:GCTTA:G	donor_loss	1.0000
20:22584187:CTTA:C	donor_loss	1.0000
20:22584188:TTACC:T	donor_loss	1.0000
20:22584189:TAC:T	donor_loss	1.0000
20:22584190:A:T	donor_loss	1.0000
20:22584262:C:CC	acceptor_gain	1.0000
20:22584270:CGAG:C	acceptor_gain	1.0000
20:22583152:GCC:G	acceptor_gain	0.9900
20:22583153:CCC:C	acceptor_gain	0.9900
20:22583155:C:CC	acceptor_gain	0.9900
20:22583159:G:T	acceptor_gain	0.9900
20:22583162:C:CT	acceptor_gain	0.9900
20:22583170:C:CT	acceptor_gain	0.9900
20:22583503:A:AC	donor_gain	0.9900
20:22583504:C:CC	donor_gain	0.9900
20:22584191:CCT:C	donor_gain	0.9900
20:22584258:CATA:C	acceptor_gain	0.9900
20:22584260:TA:T	acceptor_gain	0.9900
20:22584269:CCGAG:C	acceptor_gain	0.9900
20:22584270:C:T	acceptor_gain	0.9900
20:22584273:G:GC	acceptor_gain	0.9900

AlphaMissense

3058 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:22582082:A:G	L381P	1.000
20:22582091:A:G	I378T	1.000
20:22582091:A:T	I378N	1.000
20:22582096:G:C	F376L	1.000
20:22582096:G:T	F376L	1.000
20:22582097:A:C	F376C	1.000
20:22582097:A:G	F376S	1.000
20:22582098:A:G	F376L	1.000
20:22582098:A:T	F376I	1.000
20:22582459:G:C	F255L	1.000
20:22582459:G:T	F255L	1.000
20:22582460:A:C	F255C	1.000
20:22582460:A:G	F255S	1.000
20:22582461:A:C	F255V	1.000
20:22582461:A:G	F255L	1.000
20:22582461:A:T	F255I	1.000
20:22582463:C:T	R254H	1.000
20:22582464:G:A	R254C	1.000
20:22582464:G:T	R254S	1.000
20:22582465:C:A	K253N	1.000
20:22582465:C:G	K253N	1.000
20:22582466:T:A	K253M	1.000
20:22582467:T:C	K253E	1.000
20:22582468:C:A	Q252H	1.000
20:22582468:C:G	Q252H	1.000
20:22582472:C:A	R251L	1.000
20:22582472:C:G	R251P	1.000
20:22582472:C:T	R251H	1.000
20:22582473:G:A	R251C	1.000
20:22582473:G:C	R251G	1.000

dbSNP variants (sampled 300 via entrez): RS1000160923 (20:22584371 C>A,G,T), RS1000296086 (20:22584531 G>A,T), RS1000920736 (20:22582825 C>T), RS1001196477 (20:22586367 A>C,G), RS1002170329 (20:22581791 C>G,T), RS1002307630 (20:22582072 C>G,T), RS1002488255 (20:22587301 G>A,C), RS1002653571 (20:22580605 G>A,C), RS1002917265 (20:22585257 GA>G), RS1003275318 (20:22585409 G>C), RS1003901436 (20:22586205 G>A), RS1005257770 (20:22584765 A>T), RS1005325484 (20:22585637 G>A), RS1005407512 (20:22584010 T>C), RS1005476825 (20:22584530 C>T)

Disease associations

OMIM: gene MIM:600288 | disease phenotypes: MIM:613038

GenCC curated gene-disease

Disease	Classification	Inheritance
hyperinsulinism	Strong	Autosomal dominant
combined pituitary hormone deficiencies, genetic form	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
combined pituitary hormone deficiencies, genetic form	Moderate	AD

Mondo (3): non-acquired combined pituitary hormone deficiency (MONDO:0018762), combined pituitary hormone deficiencies, genetic form (MONDO:0013099), hyperinsulinism (MONDO:0002177)

Orphanet (2): Non-acquired combined pituitary hormone deficiency (Orphanet:467), Combined pituitary hormone deficiencies, genetic forms (Orphanet:95494)

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000044	Hypogonadotropic hypogonadism
HP:0000141	Amenorrhea
HP:0000457	Depressed nasal ridge
HP:0000478	Abnormality of the eye
HP:0000609	Optic nerve hypoplasia
HP:0000789	Infertility
HP:0000823	Delayed puberty
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000839	Pituitary dwarfism
HP:0000938	Osteopenia
HP:0001250	Seizure
HP:0001274	Agenesis of corpus callosum
HP:0001331	Absent septum pellucidum
HP:0001360	Holoprosencephaly
HP:0001510	Growth delay
HP:0001943	Hypoglycemia
HP:0002019	Constipation
HP:0002615	Hypotension
HP:0002750	Delayed skeletal maturation
HP:0002920	Decreased circulating ACTH concentration
HP:0004637	Decreased cervical spine mobility
HP:0005625	Osteoporosis of vertebrae
HP:0008187	Absence of secondary sex characteristics
HP:0008245	Pituitary hypothyroidism
HP:0008734	Decreased testicular size
HP:0009099	Median cleft palate
HP:0009888	Abnormality of secondary sexual hair
HP:0010311	Aplasia/Hypoplasia of the breasts
HP:0010442	Polydactyly
HP:0010626	Anterior pituitary agenesis

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST000591_1	Fasting plasma glucose	2.000000e-11
GCST001356_28	Gout	1.000000e-07
GCST001527_3	Fasting blood glucose (BMI interaction)	2.000000e-12
GCST001548_7	Male-pattern baldness	2.000000e-39
GCST002586_14	Fasting plasma glucose	2.000000e-12
GCST002819_1	Adolescent idiopathic scoliosis	3.000000e-08
GCST003191_1	Vitamin D levels	4.000000e-09
GCST003983_2	Male-pattern baldness	3.000000e-81
GCST003988_18	Hypothyroidism	5.000000e-10
GCST003996_23	Monobrow	4.000000e-09
GCST005186_9	Fasting blood glucose	6.000000e-09
GCST006867_84	Type 2 diabetes	3.000000e-08
GCST008362_38	Birth weight	9.000000e-10
GCST010118_76	Type 2 diabetes	2.000000e-09
GCST010241_285	Apolipoprotein A1 levels	6.000000e-09
GCST010989_157	Body size at age 10	3.000000e-08
GCST011587_18	Fasting blood glucose	3.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007906	synophrys measurement
EFO:0004344	birth weight
EFO:0004614	apolipoprotein A 1 measurement
EFO:0009819	comparative body size at age 10, self-reported

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006946	Hyperinsulinism	C18.452.394.968

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

56 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, affects expression, affects methylation	6
Valproic Acid	decreases expression, increases methylation, affects expression	5
Tretinoin	increases expression, affects expression	3
cylindrospermopsin	increases expression, decreases expression	2
Acetaminophen	decreases expression	2
Estradiol	decreases expression, increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	increases abundance, increases expression, affects cotreatment	2
bisphenol F	increases expression	1
UNC1999	decreases expression, decreases reaction	1
methylmercuric chloride	increases expression	1
nitrofen	decreases expression, decreases reaction	1
geraniol	decreases expression	1
arsenite	increases methylation	1
zinc chloride	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression	1
perfluorooctanoic acid	decreases expression	1
baicalin	decreases expression	1
arsenic trichloride	affects binding, decreases reaction	1
monoisoamyl-2,3-dimercaptosuccinate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
NSC668394	decreases expression	1
Resveratrol	decreases expression, increases expression	1
Air Pollutants	increases abundance, increases expression	1
Cadmium	decreases expression, decreases reaction	1

Cellosaurus cell lines

11 cell lines: 7 cancer cell line, 3 embryonic stem cell, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A1W5	SEES3-1V human FOXA2, clone1	Embryonic stem cell	Male
CVCL_A1W6	SEES3-1V human FOXA2, clone2	Embryonic stem cell	Male
CVCL_A1W7	SEES3-1V human FOXA2, clone3	Embryonic stem cell	Male
CVCL_B1SC	Abcam HeLa FOXA2 KO	Cancer cell line	Female
CVCL_B8GC	Abcam HCT 116 FOXA2 KO	Cancer cell line	Male
CVCL_B9IL	Abcam A-549 FOXA2 KO	Cancer cell line	Male
CVCL_D1SJ	Abcam U-87MG FOXA2 KO	Cancer cell line	Male
CVCL_D2F6	Abcam MCF-7 FOXA2 KO	Cancer cell line	Female
CVCL_D3XF	HepG2/8F_HS	Cancer cell line	Male
CVCL_E1XS	HAP1 FOXA2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

38 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00004700	PHASE2	COMPLETED	Phase II Long Term, Randomized Study of Recombinant Human Insulin-like Growth Factor I in Children With Hyperinsulinism
NCT00151684	PHASE2	COMPLETED	Diazoxide-Mediated Insulin Suppression in Hyperinsulinemic Obese Men
NCT00674440	PHASE2	COMPLETED	Utility of [F-18] fluoroDOPA for Neonatal Hyperinsulinism
NCT03053284	PHASE2	WITHDRAWN	Pasireotide in Hyperinsulinemic Hypoglycemia
NCT04062890	PHASE2	WITHDRAWN	Inhibiting GABA Transaminase to Relieve Obesity Induced Hyperinsulinemia and Insulin Resistance
NCT05088798	PHASE2	RECRUITING	Utility of 18FDOPA PET/MRI for Focal Hyperinsulinism
NCT05989347	PHASE1	RECRUITING	Study to Evaluate Biomarkers and Safety of Dapagliflozin Concomitant With Neoadjuvant Therapy
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT02524639	PHASE1/PHASE2	WITHDRAWN	Sirolimus for the Treatment of Hyperinsulinism
NCT05753657	EARLY_PHASE1	RECRUITING	A Pilot Study of Monitoring Insulin Levels and Treating Hyperinsulinemia and Hyperglycemia With Pioglitazone in Patients Treated With Alpelisib for Metastatic Breast Cancer.
NCT00004699	Not specified	COMPLETED	Dose Ranging Study of Recombinant Human Insulin-like Growth Factor I in Children With Hyperinsulinism
NCT00004825	Not specified	COMPLETED	Short Term Study of Recombinant Human Insulin-like Growth Factor I in Children With Hyperinsulinism
NCT00005104	Not specified	COMPLETED	Randomized Study of Decreased Hyperinsulinemia on the Ovulatory Response to Clomiphene Citrate in Women With Polycystic Ovary Syndrome
NCT00005365	Not specified	COMPLETED	Central Obesity and Disease Risk in Japanese Americans
NCT00005380	Not specified	COMPLETED	Insulin, Androgen, and Risk in African-American Women
NCT00005530	Not specified	COMPLETED	Diet, Insulin Resistance, and Cardiovascular Risk
NCT00005654	Not specified	COMPLETED	Randomized Study of the Effect of Decreased Hyperinsulinemia on the Ovulatory Response to Clomiphene Citrate in Obese Women With Polycystic Ovary Syndrome
NCT00005709	Not specified	COMPLETED	Lipoprotein Metabolism in Hypertensive African-Americans
NCT00073775	Not specified	COMPLETED	Epidemiology of Stress and the Metabolic Syndrome
NCT00074451	Not specified	COMPLETED	Genomewide Search for Loci Underlying Metabolic Syndrome
NCT00937079	Not specified	COMPLETED	Whole Body 111In-exendin-4 Imaging Study in Insulinoma Patients
NCT02248272	Not specified	COMPLETED	Effect of Meal Frequency on Glycemic Control of People at High Risk or Diagnosed With Diabetes
NCT03303196	Not specified	COMPLETED	Bionic Pancreas in Children With Hyperinsulinism and Post-Pancreatectomy Diabetes
NCT03358745	Not specified	COMPLETED	Impact of Meal Order on Postprandial Cardiometabolic Risk Markers
NCT03856606	Not specified	COMPLETED	The Effects of Interrupting Prolonged Sitting With Intermittent Exercise on Postprandial Lipemia
NCT04327245	Not specified	COMPLETED	To Compare the Effects of Non-nutritive Sweeteners Intake in Woman With Insulin Resistance
NCT04744896	Not specified	UNKNOWN	Effects Of Combined Cryolipolysis And High Intensity Interval Training On Insulin Resistance And Body Composition In Polycystic Ovarian Patients
NCT05329337	Not specified	COMPLETED	Link Between the Peripheral Mononuclear Cells’ Capacity to Induce Insulin Resistance and Hyperinsulinemia
NCT05528874	Not specified	COMPLETED	NUTRACORE, Glycaemic Index and Appetite
NCT05543083	Not specified	RECRUITING	Cognitive-Behavioral Therapy and Exercise Training in Adolescents At-Risk for Type 2 Diabetes
NCT05662189	Not specified	RECRUITING	Assessment of Pancreatic Beta Cell Mass and Function by Positron Emission Tomography Imaging in Human Diabetes Mellitus
NCT05764200	Not specified	RECRUITING	Acute Microbial Switch
NCT05774613	Not specified	UNKNOWN	Effect of Hibiscus Sabdariffa Beverage
NCT05950282	Not specified	RECRUITING	Determinants of Insulin Sensitivity by Age, Sex, Race/Ethnicity, BMI, and PCOS Diagnosis
NCT06363929	Not specified	TERMINATED	Continuous Glucose Monitoring in Neonatal Hyperinsulinism
NCT06478121	Not specified	RECRUITING	Understanding Beta Cell Disorders Through the Study of Rare Genotypes (ENDURE)
NCT06889454	Not specified	RECRUITING	Cardiovascular and Endothelial Markers During OGTT Before and at Six and Twelve Months Post-treatment in Women With PCOS
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes