FOXN4

Summary

FOXN4 (forkhead box N4, HGNC:21399) is a protein-coding gene on chromosome 12q24.11, encoding Forkhead box protein N4 (Q96NZ1). Transcription factor essential for neural and some non-neural tissues development, such as retina and lung respectively.

Members of the winged-helix/forkhead family of transcription factors, such as FOXN4, are characterized by a 110-amino acid DNA-binding domain that can fold into a variant of the helix-turn-helix motif consisting of 3 alpha helices flanked by 2 large loops or wings. These transcription factors are involved in a variety of biologic processes as key regulators in development and metabolism (Li et al., 2004 [PubMed 15363391]).

Source: NCBI Gene 121643 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 79 total
• MANE Select transcript: NM_213596

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21399
Approved symbol	FOXN4
Name	forkhead box N4
Location	12q24.11
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000139445
Ensembl biotype	protein_coding
OMIM	609429
Entrez	121643

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 nonsense_mediated_decay

ENST00000299162, ENST00000355216, ENST00000423960, ENST00000468516

RefSeq mRNA: 1 — MANE Select: NM_213596 NM_213596

CCDS: CCDS9126

Canonical transcript exons

ENST00000299162 — 10 exons

Exon	Start	End
ENSE00000938176	109287397	109287524
ENSE00000997899	109288056	109288180
ENSE00001100117	109287844	109287954
ENSE00001475300	109290141	109290286
ENSE00001909721	109277978	109279930
ENSE00003646855	109285304	109285511
ENSE00003657060	109308236	109308324
ENSE00003664119	109286648	109286744
ENSE00003681766	109281407	109281799
ENSE00003845146	109309119	109309284

Expression profiles

Bgee: expression breadth ubiquitous, 104 present calls, max score 84.94.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1617 / max 16.2764, expressed in 83 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133188	0.0588	29
133189	0.0573	34
133187	0.0456	20

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	84.94	gold quality
ganglionic eminence	UBERON:0004023	83.37	gold quality
buccal mucosa cell	CL:0002336	80.04	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.64	gold quality
left testis	UBERON:0004533	76.61	gold quality
right testis	UBERON:0004534	76.15	gold quality
testis	UBERON:0000473	74.57	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.28	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	71.71	gold quality
nasal cavity epithelium	UBERON:0005384	70.80	gold quality
sperm	CL:0000019	68.45	gold quality
gingival epithelium	UBERON:0001949	67.27	gold quality
gingiva	UBERON:0001828	66.37	gold quality
tendon of biceps brachii	UBERON:0008188	66.21	gold quality
secondary oocyte	CL:0000655	65.94	gold quality
oocyte	CL:0000023	65.58	gold quality
myocardium	UBERON:0002349	64.99	gold quality
cardia of stomach	UBERON:0001162	64.77	gold quality
superficial temporal artery	UBERON:0001614	64.64	gold quality
vastus lateralis	UBERON:0001379	64.53	gold quality
quadriceps femoris	UBERON:0001377	64.46	gold quality
subthalamic nucleus	UBERON:0001906	64.42	gold quality
deltoid	UBERON:0001476	64.21	gold quality
cortical plate	UBERON:0005343	64.19	gold quality
superior surface of tongue	UBERON:0007371	63.79	gold quality
saphenous vein	UBERON:0007318	63.55	gold quality
tongue	UBERON:0001723	63.49	gold quality
pericardium	UBERON:0002407	63.49	gold quality
pharyngeal mucosa	UBERON:0000355	63.32	gold quality
dorsal plus ventral thalamus	UBERON:0001897	63.30	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.43

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
ASCL1	Unknown
DLL4	Activation
NEUROD1	Activation
NEUROD4	Activation
NR4A2	Unknown
PANK2	Unknown
PROX1	Activation
PTF1A	Activation

Upstream regulators (CollecTRI, top): MEIS1

miRNA regulators (miRDB)

59 targeting FOXN4, 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-5692A	100.00	74.40	6850
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-182-3P	99.57	67.57	825
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-501-3P	99.33	66.12	651
HSA-MIR-502-3P	99.33	66.12	651
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-3922-3P	99.25	64.96	1136

Literature-anchored findings (GeneRIF, showing 1)

• FOXN4 affects myocardial ischemia-reperfusion injury through HIF-1alpha/MMP2-mediated ferroptosis of cardiomyocytes. (PMID:37605566)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxn4	ENSDARG00000010591
mus_musculus	Foxn4	ENSMUSG00000042002
rattus_norvegicus	Foxn4	ENSRNOG00000000691

Paralogs (2): FOXN3 (ENSG00000053254), FOXN2 (ENSG00000170802)

Protein

Protein identifiers

Forkhead box protein N4 — Q96NZ1 (reviewed: Q96NZ1)

All UniProt accessions (3): A0A0C4DG65, Q96NZ1, S4R3U5

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor essential for neural and some non-neural tissues development, such as retina and lung respectively. Binds to an 11-bp consensus sequence containing the invariant tetranucleotide 5’-ACGC-3’. During development of the central nervous system, is required to specify the amacrine and horizontal cell fates from multipotent retinal progenitors while suppressing the alternative photoreceptor cell fates through activating DLL4-NOTCH signaling. Also acts synergistically with ASCL1/MASH1 to activate DLL4-NOTCH signaling and drive commitment of p2 progenitors to the V2b interneuron fates during spinal cord neurogenesis. In development of non-neural tissues, plays an essential role in the specification of the atrioventricular canal and is indirectly required for patterning the distal airway during lung development.

Subcellular location. Nucleus.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96NZ1-1	1	yes
Q96NZ1-2	2
Q96NZ1-3	3

RefSeq proteins (1): NP_998761* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001766	Fork_head_dom	Domain
IPR030456	TF_fork_head_CS_2	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR047119	FOXN2/3-like	Family

Pfam: PF00250

UniProt features (9 total): splice variant 4, region of interest 2, chain 1, DNA-binding region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96NZ1-F1	58.22	0.22

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 100 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_NEUROGENESIS, GOBP_NEURAL_RETINA_DEVELOPMENT, GOBP_CELL_DIFFERENTIATION_IN_SPINAL_CORD, GOBP_DORSAL_VENTRAL_PATTERN_FORMATION, GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_VENTRAL_SPINAL_CORD_DEVELOPMENT, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EMBRYONIC_HEART_TUBE_DEVELOPMENT, GOBP_EMBRYONIC_ORGAN_MORPHOGENESIS, GOBP_HEART_MORPHOGENESIS, GOBP_CENTRAL_NERVOUS_SYSTEM_NEURON_DIFFERENTIATION

GO Biological Process (11): heart looping (GO:0001947), regulation of DNA-templated transcription (GO:0006355), regulation of heart contraction (GO:0008016), retina layer formation (GO:0010842), ventral spinal cord interneuron differentiation (GO:0021514), amacrine cell differentiation (GO:0035881), atrioventricular canal development (GO:0036302), positive regulation of transcription by RNA polymerase II (GO:0045944), ventral spinal cord interneuron fate commitment (GO:0060579), nervous system development (GO:0007399), neuron fate commitment (GO:0048663)

GO Molecular Function (7): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), cis-regulatory region sequence-specific DNA binding (GO:0000987), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
neural retina development	2
central nervous system neuron differentiation	2
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
binding	2
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
heart contraction	1
regulation of blood circulation	1
anatomical structure formation involved in morphogenesis	1
retina morphogenesis in camera-type eye	1
cell differentiation in spinal cord	1
ventral spinal cord development	1
heart development	1
anatomical structure development	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
spinal cord dorsal/ventral patterning	1
ventral spinal cord interneuron differentiation	1
neuron fate commitment	1
cell fate commitment involved in pattern specification	1
system development	1
neuron differentiation	1
cell fate commitment	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
regulation of DNA-templated transcription	1
transcription regulator activity	1
nucleic acid binding	1
DNA binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1328 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXN4	NEUROD4	Q9HD90	936
FOXN4	NEUROD1	Q13562	859
FOXN4	PROX1	Q92786	808
FOXN4	PTF1A	Q7RTS3	734
FOXN4	VSX2	P58304	689
FOXN4	VSX1	Q9NZR4	666
FOXN4	ATOH7	Q8N100	665
FOXN4	BARHL2	Q9NY43	632
FOXN4	POU4F2	Q12837	588
FOXN4	BHLHE22	Q8NFJ8	542
FOXN4	CRX	O43186	528
FOXN4	PAX6	P26367	518
FOXN4	ASCL1	P50553	492
FOXN4	DLL4	Q9NR61	487
FOXN4	ISL1	P20663	464

IntAct

14 interactions, top by confidence:

A	B	Type	Score
RFX2	FOXN4	psi-mi:“MI:0915”(physical association)	0.560
ATXN1	FOXN4	psi-mi:“MI:0915”(physical association)	0.560
FOXN4	AMY1A	psi-mi:“MI:0915”(physical association)	0.560
FHL3	FOXN4	psi-mi:“MI:0915”(physical association)	0.490
FOXN4	FHL3	psi-mi:“MI:0915”(physical association)	0.490
EGLN3	FAM168B	psi-mi:“MI:0914”(association)	0.350
FOXN4	GABARAP	psi-mi:“MI:0914”(association)	0.350
ATXN1	FOXN4	psi-mi:“MI:0915”(physical association)	0.000
FOXN4	RFX2	psi-mi:“MI:0915”(physical association)	0.000
RFX2	FOXN4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): AMY1C (Affinity Capture-MS), GABARAP (Affinity Capture-MS), FOXN4 (Affinity Capture-MS), FOXN4 (Two-hybrid), FOXN4 (Two-hybrid), FOXN4 (Two-hybrid), AMY1C (Affinity Capture-MS), LMBRD1 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A1L8H0H2, A2BGM5, A3KNJ3, F1QDF8, F1R8Z9, F8VPJ6, O00409, O75030, P59667, P70056, P79269, Q08050, Q1KKS7, Q1KL10, Q28D67, Q28EM1, Q28EW4, Q28GC4, Q2KHR2, Q32NH9, Q33BP8, Q3BJS1, Q3UHX8, Q499D0, Q4G112, Q503Z8, Q5M7N6, Q5W1J6, Q5WM45, Q61321, Q66IG8, Q68EZ2, Q6NVT7, Q708W1, Q708W2, Q7T1C0, Q8AWZ2, Q8IVH2, Q8K3Q3, Q91904

Diamond homologs: A0A8V0YY16, A1L1S5, A2BGM5, A8MTJ6, B5RHS5, D3Z120, O00358, O00409, O15353, O54743, O60129, O70220, O88470, O93529, P32027, P32028, P32030, P32314, P42128, P55316, P56260, P58012, Q00939, Q12946, Q12947, Q12948, Q12951, Q13461, Q1A1A1, Q1A1A2, Q1A1A3, Q1A1A4, Q1A1A5, Q1A1A6, Q28BS5, Q28D67, Q28F43, Q28G71, Q28H65, Q28HT3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FOXN4	“up-regulates quantity by expression”	PTF1A	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	76
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1091 predictions. Top by Δscore:

Variant	Effect	Δscore
12:109281405:AC:A	donor_gain	1.0000
12:109281406:CC:C	donor_gain	1.0000
12:109285320:C:CA	donor_gain	1.0000
12:109285343:T:TA	donor_gain	1.0000
12:109285507:GCCGT:G	acceptor_gain	1.0000
12:109285508:CCGT:C	acceptor_gain	1.0000
12:109285508:CCGTC:C	acceptor_gain	1.0000
12:109285509:CGT:C	acceptor_gain	1.0000
12:109285509:CGTC:C	acceptor_gain	1.0000
12:109285510:GT:G	acceptor_gain	1.0000
12:109285512:C:CC	acceptor_gain	1.0000
12:109285512:C:CG	acceptor_loss	1.0000
12:109285513:T:C	acceptor_loss	1.0000
12:109286643:CTCA:C	donor_loss	1.0000
12:109286644:TCACC:T	donor_loss	1.0000
12:109286645:CACC:C	donor_loss	1.0000
12:109286646:A:AC	donor_gain	1.0000
12:109286647:C:CA	donor_loss	1.0000
12:109286647:C:CC	donor_gain	1.0000
12:109286742:CAG:C	acceptor_gain	1.0000
12:109287542:C:CT	acceptor_gain	1.0000
12:109287543:A:T	acceptor_gain	1.0000
12:109287552:G:C	acceptor_gain	1.0000
12:109287552:G:GC	acceptor_gain	1.0000
12:109290136:CCTA:C	donor_loss	1.0000
12:109290139:A:AG	donor_loss	1.0000
12:109290140:C:A	donor_loss	1.0000
12:109290191:G:A	donor_gain	1.0000
12:109309115:GTAC:G	donor_loss	1.0000
12:109309117:AC:A	donor_loss	1.0000

AlphaMissense

3366 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:109285400:C:G	A269P	1.000
12:109285401:C:A	W268C	1.000
12:109285401:C:G	W268C	1.000
12:109285402:C:G	W268S	1.000
12:109285403:A:G	W268R	1.000
12:109285403:A:T	W268R	1.000
12:109285446:C:A	K253N	1.000
12:109285446:C:G	K253N	1.000
12:109285448:T:C	K253E	1.000
12:109285452:G:C	F251L	1.000
12:109285452:G:T	F251L	1.000
12:109285453:A:C	F251C	1.000
12:109285453:A:G	F251S	1.000
12:109285454:A:C	F251V	1.000
12:109285454:A:G	F251L	1.000
12:109285454:A:T	F251I	1.000
12:109285465:A:G	L247P	1.000
12:109285471:A:C	L245R	1.000
12:109285471:A:G	L245P	1.000
12:109285471:A:T	L245Q	1.000
12:109285473:G:C	N244K	1.000
12:109285473:G:T	N244K	1.000
12:109285474:T:A	N244I	1.000
12:109285475:T:C	N244D	1.000
12:109285476:G:C	H243Q	1.000
12:109285476:G:T	H243Q	1.000
12:109285477:T:A	H243L	1.000
12:109285477:T:C	H243R	1.000
12:109285477:T:G	H243P	1.000
12:109285478:G:A	H243Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000034527 (12:109290698 A>T), RS1000057991 (12:109284644 G>A), RS1000206568 (12:109308504 G>A), RS1000237766 (12:109307989 A>C), RS1000286606 (12:109284398 G>C,T), RS1000360540 (12:109284109 C>T), RS1000542592 (12:109310446 G>A), RS1000563433 (12:109308389 A>C), RS1000571985 (12:109309664 G>A), RS1000700778 (12:109282580 C>T), RS1000838845 (12:109288346 T>A), RS1001035416 (12:109303364 C>G,T), RS1001129228 (12:109290591 C>T), RS1001244868 (12:109300932 G>A), RS1001329226 (12:109284151 A>G)

Disease associations

OMIM: gene MIM:609429 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST006941_4	Irritable mood	1.000000e-09
GCST006951_4	Feeling hurt	9.000000e-10
GCST010135_11	Oily fish consumption	6.000000e-11
GCST010135_3	Oily fish consumption	7.000000e-17
GCST010140_3	Pork consumption	6.000000e-11
GCST010140_47	Pork consumption	7.000000e-17
GCST010142_62	Fish- and plant-related diet	4.000000e-13
GCST010142_83	Fish- and plant-related diet	4.000000e-08
GCST010142_87	Fish- and plant-related diet	2.000000e-19
GCST010142_94	Fish- and plant-related diet	5.000000e-13

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009594	irritability measurement
EFO:0009599	feeling emotionally hurt measurement
EFO:0008111	diet measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects binding, increases reaction, increases expression	2
propionaldehyde	increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	decreases methylation	1
ferrous chloride	decreases expression	1
beta-methylcholine	affects expression	1
pentanal	increases expression	1
2-palmitoylglycerol	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Aldehydes	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
DEET	increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Methapyrilene	decreases methylation	1
Methylcholanthrene	increases expression, affects binding, increases reaction	1
Phenobarbital	affects expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Tunicamycin	decreases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Zinc Sulfate	increases expression	1
Okadaic Acid	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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