TFAP2E

Summary

TFAP2E (transcription factor AP-2 epsilon, HGNC:30774) is a protein-coding gene on chromosome 1p34.3, encoding Transcription factor AP-2-epsilon (Q6VUC0). Sequence-specific DNA-binding protein that interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes.

Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in positive regulation of transcription by RNA polymerase II and regulation of cell population proliferation. Predicted to be located in chromatin. Predicted to be active in nucleus.

Source: NCBI Gene 339488 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple congenital anomalies/dysmorphic syndrome (Limited, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 92 total
• MANE Select transcript: NM_178548

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30774
Approved symbol	TFAP2E
Name	transcription factor AP-2 epsilon
Location	1p34.3
Locus type	gene with protein product
Status	Approved
Aliases	AP2E, AP-2epsilon
Ensembl gene	ENSG00000116819
Ensembl biotype	protein_coding
OMIM	614428
Entrez	339488

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 retained_intron, 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000373235, ENST00000650429, ENST00000682155, ENST00000683984, ENST00000684707

RefSeq mRNA: 1 — MANE Select: NM_178548 NM_178548

CCDS: CCDS393

Canonical transcript exons

ENST00000373235 — 7 exons

Exon	Start	End
ENSE00000765296	35589930	35590048
ENSE00000765297	35590634	35590775
ENSE00001144635	35588330	35588552
ENSE00001334423	35594394	35595328
ENSE00001340237	35574949	35575000
ENSE00001340242	35573927	35574409
ENSE00001340245	35573314	35573604

Expression profiles

Bgee: expression breadth ubiquitous, 170 present calls, max score 93.00.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0901 / max 12.5491, expressed in 37 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
201463	0.0901	37

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	93.00	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.88	gold quality
cerebellar cortex	UBERON:0002129	92.77	gold quality
cerebellum	UBERON:0002037	91.37	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.78	gold quality
right frontal lobe	UBERON:0002810	81.42	gold quality
Brodmann (1909) area 9	UBERON:0013540	79.26	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	78.69	gold quality
granulocyte	CL:0000094	78.09	gold quality
nucleus accumbens	UBERON:0001882	77.16	gold quality
skin of leg	UBERON:0001511	76.96	gold quality
anterior cingulate cortex	UBERON:0009835	76.51	gold quality
putamen	UBERON:0001874	76.36	gold quality
spinal cord	UBERON:0002240	76.06	gold quality
caudate nucleus	UBERON:0001873	75.74	gold quality
hypothalamus	UBERON:0001898	75.64	gold quality
skin of abdomen	UBERON:0001416	75.63	gold quality
amygdala	UBERON:0001876	74.45	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	74.12	gold quality
zone of skin	UBERON:0000014	74.01	gold quality
brain	UBERON:0000955	72.90	gold quality
right uterine tube	UBERON:0001302	72.52	gold quality
leukocyte	CL:0000738	72.19	gold quality
monocyte	CL:0000576	71.95	gold quality
ectocervix	UBERON:0012249	71.89	gold quality
forebrain	UBERON:0001890	71.07	gold quality
lower esophagus mucosa	UBERON:0035834	71.01	gold quality
primary visual cortex	UBERON:0002436	70.84	gold quality
adenohypophysis	UBERON:0002196	70.80	gold quality
tibial nerve	UBERON:0001323	70.70	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.24

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
COL2A1
CXCL1	Activation
ITGA10

JASPAR motifs

Motif	Name	Family
MA1569.1	TFAP2E	AP-2
MA1569.2	TFAP2E	AP-2

JASPAR matrix evidence (PMIDs): PMID:16420676

Upstream regulators (CollecTRI, top): SOX9

miRNA regulators (miRDB)

61 targeting TFAP2E, 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-6873-3P	100.00	71.42	2626
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-2113	99.58	71.22	1521

Literature-anchored findings (GeneRIF, showing 9)

• These findings reveal that Tfap2 activity, mediated redundantly by Tfap2a and Tfap2e, promotes melanophore differentiation in parallel with Mitf by an effector other than Kit. (PMID:20862309)
• TFAP2E hypermethylation is associated with clinical nonresponsiveness to chemotherapy in colorectal cancer. (PMID:22216841)
• AP-2epsilon indirectly interacts with the core promoter of COL2A1 and subsequently inhibits its transcriptional activity, thus modulating cartilage development. (PMID:23331625)
• AP-2E was frequently hypermethylated in tumors from patients with colorectal cancer (PMID:24996990)
• Hypermethylation of TFAP2E was associated with lack of response to fluorouracil-based chemotherapy, indicating that it might be a potential predictor of treatment response in patients with gastric cancer. (PMID:25810491)
• Results showed that lower expression levels of TFAP2E are significantly associated with a shorter survival of patients with neuroblastoma indicating that TFAP2E acts as a tumor suppressor of neuroblastoma. (PMID:28260105)
• TFAP2E methylation and expression may not play a major role in predicting response to 5-FU-based chemotherapy in patients with colorectal cancer. (PMID:29535127)
• In the present study, it was demonstrated that hypermethylation of TFAP2E resulted in its reduced expression and 5FU chemoresistance in gastric cancer (GC) cells. miRNAs miR106a5p and miR421 were highly expressed and regulated the chemoresistance induced by TFAP2E methylation. (PMID:31115533)
• Transcription factor activating enhancer-binding protein 2epsilon (AP2epsilon) modulates phenotypic plasticity and progression of malignant melanoma. (PMID:38773108)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	tfap2e	ENSDARG00000008861
mus_musculus	Tfap2e	ENSMUSG00000042477
rattus_norvegicus	Tfap2e	ENSRNOG00000027595
drosophila_melanogaster	TfAP-2	FBGN0261953
caenorhabditis_elegans		WBGENE00009202
caenorhabditis_elegans		WBGENE00009203
caenorhabditis_elegans		WBGENE00013383
caenorhabditis_elegans		WBGENE00019424

Paralogs (4): TFAP2B (ENSG00000008196), TFAP2D (ENSG00000008197), TFAP2C (ENSG00000087510), TFAP2A (ENSG00000137203)

Protein

Protein identifiers

Transcription factor AP-2-epsilon — Q6VUC0 (reviewed: Q6VUC0)

Alternative names: Activating enhancer-binding protein 2-epsilon

All UniProt accessions (1): Q6VUC0

UniProt curated annotations — full annotation on UniProt →

Function. Sequence-specific DNA-binding protein that interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes. AP-2 factors bind to the consensus sequence 5’-GCCNNNGGC-3’ and activate genes involved in a large spectrum of important biological functions including proper eye, face, body wall, limb and neural tube development. They also suppress a number of genes including MCAM/MUC18, C/EBP alpha and MYC. AP-2-epsilon may play a role in the development of the CNS and in cartilage differentiation.

Subunit / interactions. Binds DNA as a dimer. Can form homodimers or heterodimers with other AP-2 family members.

Subcellular location. Nucleus.

Tissue specificity. Expressed in skin, primary keratinocytes, immortalized keratinocytes, and HeLa cell line.

Similarity. Belongs to the AP-2 family.

RefSeq proteins (1): NP_848643* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004979	TF_AP2	Family
IPR013854	TF_AP2_C	Domain

Pfam: PF03299

UniProt features (4 total): chain 1, region of interest 1, short sequence motif 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6VUC0-F1	68.25	0.37

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 (1): 246

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-8866904	Negative regulation of activity of TFAP2 (AP-2) family transcription factors
R-HSA-8866907	Activation of the TFAP2 (AP-2) family of transcription factors
R-HSA-212436	Generic Transcription Pathway
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8864260	Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors

MSigDB gene sets: 67 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, BENPORATH_ES_WITH_H3K27ME3, CATRRAGC_UNKNOWN, chr1p34, KRIGE_RESPONSE_TO_TOSEDOSTAT_24HR_UP, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, MEISSNER_NPC_HCP_WITH_H3_UNMETHYLATED, MEISSNER_BRAIN_HCP_WITH_H3K27ME3, MIKKELSEN_MCV6_HCP_WITH_H3K27ME3, MIKKELSEN_MEF_HCP_WITH_H3K27ME3, GOBP_POSITIVE_REGULATION_OF_TRANSCRIPTION_BY_RNA_POLYMERASE_II, GOMF_DNA_BINDING_TRANSCRIPTION_ACTIVATOR_ACTIVITY, REACTOME_TRANSCRIPTIONAL_REGULATION_BY_THE_AP_2_TFAP2_FAMILY_OF_TRANSCRIPTION_FACTORS, REACTOME_NEGATIVE_REGULATION_OF_ACTIVITY_OF_TFAP2_AP_2_FAMILY_TRANSCRIPTION_FACTORS, REACTOME_ACTIVATION_OF_THE_TFAP2_AP_2_FAMILY_OF_TRANSCRIPTION_FACTORS

GO Biological Process (3): regulation of cell population proliferation (GO:0042127), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (8): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), 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 activator activity, RNA polymerase II-specific (GO:0001228), identical protein binding (GO:0042802), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	2
RNA Polymerase II Transcription	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
cell population proliferation	1
regulation of cellular process	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
protein binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
regulation of DNA-templated transcription	1
transcription regulator activity	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

508 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TFAP2E	DKK4	Q9UBT3	447
TFAP2E	C10orf71	Q711Q0	376
TFAP2E	CDHR1	Q96JP9	343
TFAP2E	BPTF	Q12830	341
TFAP2E	FAT2	Q9NYQ8	333
TFAP2E	LETMD1	Q6P1Q0	326
TFAP2E	FAXDC2	Q96IV6	323
TFAP2E	HOXB9	P17482	320
TFAP2E	SOX10	P56693	319
TFAP2E	HHIPL1	Q96JK4	305
TFAP2E	ARHGAP28	Q9P2N2	296
TFAP2E	SALL3	Q9BXA9	294
TFAP2E	BPIFC	Q8NFQ6	280
TFAP2E	BARHL2	Q9NY43	279
TFAP2E	ZIC1	Q15915	276

IntAct

16 interactions, top by confidence:

A	B	Type	Score
CCL27	TFAP2E	psi-mi:“MI:0915”(physical association)	0.370
	TFAP2E	psi-mi:“MI:0915”(physical association)	0.370
CCL4L1	TFAP2E	psi-mi:“MI:0915”(physical association)	0.370
CSF2	TFAP2E	psi-mi:“MI:0915”(physical association)	0.370
IL12B	TFAP2E	psi-mi:“MI:0915”(physical association)	0.370
IL18	TFAP2E	psi-mi:“MI:0915”(physical association)	0.370
IL20	TFAP2E	psi-mi:“MI:0915”(physical association)	0.370
IL3	TFAP2E	psi-mi:“MI:0915”(physical association)	0.370
IL37	TFAP2E	psi-mi:“MI:0915”(physical association)	0.370
TNF	TFAP2E	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (2): TFAP2E (Affinity Capture-MS), TFAP2E (Co-fractionation)

ESM2 similar proteins: A0A1B0GUA5, A0A1B0GVQ0, A0A286YF18, A0JNN8, A2VDX9, A5PK62, A6NGB7, A9CBA0, O09800, P04488, P06480, P06764, P07646, P0C171, P0DJK0, P0DJK1, P0DMQ5, P13291, P22389, P36342, P46695, P98162, Q08102, Q1RMT9, Q2HJ59, Q3TYP4, Q5BIR3, Q5EAA5, Q5JTB6, Q5NRQ0, Q6F5E0, Q6VUC0, Q6VUP9, Q703F0, Q765Z5, Q867A9, Q867D0, Q89448, Q8MJW9, Q8TEF2

Diamond homologs: A1A4R9, P05549, P34056, P58197, Q09585, Q2T9K2, Q5RJ20, Q61312, Q61313, Q6P0E7, Q6VUC0, Q6VUP9, Q76HI7, Q7Z6R9, Q91ZK0, Q92481, Q92754, Q9N0N3, G2HK15

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	80
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1371 predictions. Top by Δscore:

Variant	Effect	Δscore
1:35588328:A:AG	acceptor_gain	1.0000
1:35588329:G:GG	acceptor_gain	1.0000
1:35589896:A:AG	acceptor_gain	1.0000
1:35589897:G:GG	acceptor_gain	1.0000
1:35589897:GTT:G	acceptor_gain	1.0000
1:35589919:T:TA	acceptor_gain	1.0000
1:35589922:A:AG	acceptor_gain	1.0000
1:35589922:AT:A	acceptor_gain	1.0000
1:35589923:T:G	acceptor_gain	1.0000
1:35590046:AAGGT:A	donor_loss	1.0000
1:35590049:GTGA:G	donor_loss	1.0000
1:35590629:CCCAG:C	acceptor_loss	1.0000
1:35590632:A:AG	acceptor_gain	1.0000
1:35590632:A:AT	acceptor_loss	1.0000
1:35590633:G:GA	acceptor_loss	1.0000
1:35590633:G:GG	acceptor_gain	1.0000
1:35590633:GGAGA:G	acceptor_gain	1.0000
1:35590771:GCCAA:G	donor_gain	1.0000
1:35590773:CAAG:C	donor_loss	1.0000
1:35590774:AAGT:A	donor_loss	1.0000
1:35590775:AG:A	donor_loss	1.0000
1:35590776:G:GG	donor_gain	1.0000
1:35590776:GT:G	donor_loss	1.0000
1:35590780:G:GG	donor_gain	1.0000
1:35573602:ATGG:A	donor_loss	0.9900
1:35573603:TG:T	donor_gain	0.9900
1:35573604:GG:G	donor_gain	0.9900
1:35573605:G:GA	donor_loss	0.9900
1:35573605:G:GG	donor_gain	0.9900
1:35573606:T:G	donor_loss	0.9900

AlphaMissense

2795 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:35588419:T:C	F218L	1.000
1:35588420:T:C	F218S	1.000
1:35588420:T:G	F218C	1.000
1:35588421:C:A	F218L	1.000
1:35588421:C:G	F218L	1.000
1:35588434:G:C	G223R	1.000
1:35588435:G:A	G223D	1.000
1:35588435:G:T	G223V	1.000
1:35588441:T:A	L225H	1.000
1:35588441:T:C	L225P	1.000
1:35588447:T:A	L227Q	1.000
1:35588447:T:C	L227P	1.000
1:35588450:T:A	L228H	1.000
1:35588450:T:C	L228P	1.000
1:35588452:A:C	S229R	1.000
1:35588454:C:A	S229R	1.000
1:35588454:C:G	S229R	1.000
1:35588464:A:G	K233E	1.000
1:35588467:T:G	Y234D	1.000
1:35588495:G:C	R243P	1.000
1:35588501:T:A	L245H	1.000
1:35588501:T:C	L245P	1.000
1:35588510:C:A	P248H	1.000
1:35588519:T:A	L251H	1.000
1:35588519:T:C	L251P	1.000
1:35588521:A:G	N252D	1.000
1:35588522:A:T	N252I	1.000
1:35588523:C:A	N252K	1.000
1:35588523:C:G	N252K	1.000
1:35588525:C:A	A253D	1.000

dbSNP variants (sampled 300 via entrez): RS1000198595 (1:35573870 G>A,T), RS1000235833 (1:35578568 G>A,T), RS1000494286 (1:35595648 C>T), RS1000670887 (1:35592397 T>G), RS1000981639 (1:35586362 G>A,T), RS1001098815 (1:35579451 T>G), RS1001230274 (1:35592147 T>C), RS1001279575 (1:35579031 G>A), RS1001343971 (1:35595345 T>C), RS1001380443 (1:35588868 C>T), RS1001693418 (1:35575518 G>A,C), RS1001871761 (1:35575831 T>C), RS1001898496 (1:35595019 A>T), RS1002031381 (1:35590396 G>A,T), RS1002170724 (1:35573094 C>A)

Disease associations

OMIM: gene MIM:614428 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple congenital anomalies/dysmorphic syndrome	Limited	Autosomal dominant

Mondo (1): multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042)

Orphanet (1): Multiple congenital anomalies/dysmorphic syndrome (Orphanet:68341)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002396_125	Mean reticulocyte volume	3.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010701	mean reticulocyte volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression	1
sodium arsenite	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
jinfukang	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	decreases expression	1
Acrylamide	increases expression	1

Clinical trials (associated diseases)

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