FOXO4

Summary

FOXO4 (forkhead box O4, HGNC:7139) is a protein-coding gene on chromosome Xq13.1, encoding Forkhead box protein O4 (P98177). Transcription factor involved in the regulation of the insulin signaling pathway.

This gene encodes a member of the O class of winged helix/forkhead transcription factor family. Proteins encoded by this class are regulated by factors involved in growth and differentiation indicating they play a role in these processes. A translocation involving this gene on chromosome X and the homolog of the Drosophila trithorax gene, encoding a DNA binding protein, located on chromosome 11 is associated with leukemia. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4303 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 88 total
• Transcription factor: yes — 37 downstream targets (CollecTRI)
• MANE Select transcript: NM_005938

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7139
Approved symbol	FOXO4
Name	forkhead box O4
Location	Xq13.1
Locus type	gene with protein product
Status	Approved
Aliases	AFX1
Ensembl gene	ENSG00000184481
Ensembl biotype	protein_coding
OMIM	300033
Entrez	4303

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000341558, ENST00000374259, ENST00000464598, ENST00000466874

RefSeq mRNA: 2 — MANE Select: NM_005938 NM_001170931, NM_005938

CCDS: CCDS43969, CCDS55440

Canonical transcript exons

ENST00000374259 — 3 exons

Exon	Start	End
ENSE00001321000	71100684	71101740
ENSE00001462943	71102077	71103532
ENSE00001892186	71095851	71096981

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 96.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.3029 / max 929.2473, expressed in 1305 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196642	4.8678	871
196643	1.5786	638
196646	0.3191	71
196644	0.2808	118
196645	0.2565	105

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	96.89	gold quality
type B pancreatic cell	CL:0000169	95.74	silver quality
olfactory bulb	UBERON:0002264	95.46	silver quality
gastrocnemius	UBERON:0001388	93.27	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.25	gold quality
amygdala	UBERON:0001876	93.23	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.95	gold quality
medial globus pallidus	UBERON:0002477	92.87	gold quality
putamen	UBERON:0001874	92.85	gold quality
globus pallidus	UBERON:0001875	92.81	gold quality
muscle of leg	UBERON:0001383	92.73	gold quality
spinal cord	UBERON:0002240	92.10	gold quality
diaphragm	UBERON:0001103	91.98	silver quality
lateral globus pallidus	UBERON:0002476	91.96	gold quality
tongue squamous epithelium	UBERON:0006919	91.72	silver quality
parotid gland	UBERON:0001831	91.57	silver quality
substantia nigra	UBERON:0002038	91.46	gold quality
lateral nuclear group of thalamus	UBERON:0002736	91.46	gold quality
muscle organ	UBERON:0001630	91.38	gold quality
vena cava	UBERON:0004087	91.37	gold quality
right adrenal gland cortex	UBERON:0035827	91.36	gold quality
cervix squamous epithelium	UBERON:0006922	91.28	silver quality
right adrenal gland	UBERON:0001233	91.17	gold quality
midbrain	UBERON:0001891	91.15	gold quality
left adrenal gland	UBERON:0001234	91.02	gold quality
adrenal cortex	UBERON:0001235	90.91	gold quality
left adrenal gland cortex	UBERON:0035825	90.86	gold quality
placenta	UBERON:0001987	90.53	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	90.51	gold quality
blood	UBERON:0000178	90.42	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	126.86
E-ANND-3	no	2.05

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

37 targets.

Target	Regulation
AKT1
ANXA8	Activation
ANXA8L1	Repression
ATXN3
BCL2L11	Activation
BCL6	Activation
CCNG2	Activation
CDKN1A	Unknown
CDKN1B	Activation
CREB1	Activation
CYP51A1	Unknown
EPO	Repression
FBXO32	Activation
G6PC1	Unknown
GADD45A	Activation
HIF1A	Repression
IDH1	Unknown
IGFBP1	Activation
IL10	Activation
INS
MMP9	Activation
MYLK
PCK2	Unknown
PPARGC1A	Activation
PSMD11	Unknown
RBL2	Activation
SCP2	Unknown
SERPINE1	Activation
SIRT1
SOD2	Activation

JASPAR motifs

Motif	Name	Family
MA0848.1	FOXO4	FOX

JASPAR matrix evidence (PMIDs): PMID:10880363

Upstream regulators (CollecTRI, top): FOXO3, FOXS1, MYC, NR0B2, TSC22D3

miRNA regulators (miRDB)

113 targeting FOXO4, 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-4673	100.00	66.64	1490
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6764-5P	99.75	67.89	2304

Literature-anchored findings (GeneRIF, showing 40)

• The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor. (PMID:11777915)
• AFX zeta is a downstream target of both the phosphatidylinositol 3-kinase/PKB insulin signaling pathway and an AMP-activated protein kinase-dependent pathway. (PMID:11779849)
• Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors (PMID:11884591)
• the MLL-AFX fusion protein requires the transcriptional effector domains of AFX to transform myeloid progenitors and interfere with forkhead protein function (PMID:12192052)
• FOXO4 induces the down-regulation of hypoxia-inducible factor 1 alpha by a von Hippel-Lindau protein-independent mechanism (PMID:12761217)
• fMLP-stimulated neutrophils coordinate the regulation of FOXO transcription factors and the survival factor Mcl-1, a mechanism that may allow neutrophils to alter their survival. (PMID:12960271)
• CBP-induced acetylation of AFX is a novel modification mechanism by which AFX keeps the transcriptional activity mitigating in the nucleus (PMID:12964026)
• Phosphorylation of FOXO4 by protein kinase B on threonine-28 and serine-193 leads to a tight association of FOXO4 with 14-3-3 zeta, causing complete inhibition of DNA binding, most likely by masking of the DNA binding surface of Forkhead domain by 14-3-3. (PMID:14690436)
• Data demonstrate that acetylation functions in a second pathway of negative control for FOXO factors and provides a novel mechanism whereby hSir2(SIRT1) can promote cellular survival and increase lifespan. (PMID:15126506)
• Data show that low levels of oxidative stress generated by treatment with hydrogen peroxide induce the activation of FOXO4. (PMID:15538382)
• Introduction of dominant-negative FoxO into mousse cells partially rescues cAMP-induced inhibition of proliferation. (PMID:15688004)
• FOXO4 gene as a novel anticancer agent for HER2-overexpressing cells. (PMID:15688030)
• results show that Forkhead transcription factor 4-dependent expression of Bim protein plays a pivotal role for endothelial progenitor cell apoptosis (PMID:15824087)
• results demonstrate a role for beta-catenin in regulating FOXO function that is particularly important under conditions of oxidative stress (PMID:15905404)
• DNA-binding domain of FoxO4 remains relatively mobile while bound to the 14-3-3 protein. (PMID:16114898)
• The patients with immunophenotype of Pre-B-acute lymphoblastic leukemia were found to carry: MLL/AFX. (PMID:16215946)
• both N- and C-terminal regions of forkhead domain are important for stability of the FoxO4-DBD.DNA complex (PMID:17244620)
• AFX splice variants exhibit dominant negative activity and inhibit AFXalpha-mediated tumor cell apoptosis (PMID:18648506)
• Mdm2 induces mono-ubiquitination of FOXO4 (PMID:18665269)
• FOXO1, FOXO3, and FOXO4 are expressed in human luteinized mural granulosa cells, which may suggest that these transcription factors are also involved in human folliculogenesis and luteinization. (PMID:18692812)
• Pin1 is identified as a novel negative FOXO regulator, interconnecting FOXO phosphorylation and monoubiquitination in response to cellular stress to regulate p27(kip1). (PMID:18794148)
• Results suggest that the expression of FOXO1 and FOXO4 genes is stimulated by FOXO3 and possibly by other FOXO factors in a positive feedback loop, which is disrupted by growth factors. (PMID:19244250)
• The model of the complex suggests that the forkhead domain of FOXO4 is docked within the central channel of the 14-3-3 protein dimer, consistent with the hypothesis that 14-3-3 masks the DNA binding interface of FOXO4. (PMID:19416966)
• FoxO4 is down-regulated in patients with inflammatory bowel disease. (PMID:19560465)
• these data provide a mechanism of FOXO4 anti-oxidative protection through O-GlcNAcylation. (PMID:19932102)
• FoxO4 acts on CYP51 to regulate the late steps of cholesterol biosynthesis. (PMID:20037138)
• Findings show that oxidative stress and FOXO4 induce PAI-1 expression through modulation of HIF-1alpha and CREB protein levels and that enhanced CREB binding to the PAI-1 promoter is critical for the PAI-1 induction under oxidative stress. (PMID:20136501)
• PKG inhibits TCF signaling in colon cancer cells by blocking beta-catenin expression and activating FOXO4. (PMID:20348951)
• a conserved critical Ku70 role for FOXO function toward coordination of a survival program (PMID:20570964)
• greater in fetal membranes obtained from the supracervical compared to distal site (PMID:20934750)
• structure of the FOXO4-DNA-binding domain (DBD)-DNA complex suggests that both direct water-DNA base contacts and the unique water-network interactions contribute to FOXO-DBD binding to the DNA in a sequence-specific manner (PMID:21123876)
• gene study of FOXO4, reveals no association with human longevity in Germans (PMID:21388494)
• demonstrated that adiponectin activated 5’-AMP-activated protein kinase alpha2 isoform, leading to inhibition of mammalian target of rapamycin complex 1 and S6K1. This in turn stabilized insulin receptor substrate-1, driving Akt2-mediated inhibition of FoxO4 (PMID:21454807)
• DEPP is regulated at the level of transcription by FoxO in human vascular endothelial cells (PMID:21510935)
• Tax induces a dose-dependent degradation of FoxO4 by the ubiquitin-proteasome pathway. (PMID:21525355)
• Findings support that ATXN3 plays an important role in regulating the FOXO4-dependent antioxidant stress response via SOD2. (PMID:21536589)
• Foxo4 may be a useful target for suppression in the treatment of HBV-associated hepatocellular carcinoma cells. (PMID:21567078)
• Studies indicate that FoxO1, 3 and 4 genes were discovered at the chromosomal breakpoints found in cancers and were initially implicated in cancer. (PMID:21613825)
• Studies indictet that the mammalian FoxO family consists of FoxO1, 3, 4 and 6 and are regulated by by AKT and 14-3-3 proteins. (PMID:21708191)
• identified FOXO4 and PDCD4 as direct and functional targets of miR-499-5p (PMID:21934092)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxo4	ENSDARG00000055792
mus_musculus	Foxo4	ENSMUSG00000042903
rattus_norvegicus	Foxo4	ENSRNOG00000033316

Paralogs (41): FOXP3 (ENSG00000049768), FOXC1 (ENSG00000054598), FOXJ2 (ENSG00000065970), FOXF1 (ENSG00000103241), FOXN1 (ENSG00000109101), FOXM1 (ENSG00000111206), FOXP1 (ENSG00000114861), FOXO3 (ENSG00000118689), FOXA2 (ENSG00000125798), 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), 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

Forkhead box protein O4 — P98177 (reviewed: P98177)

Alternative names: Fork head domain transcription factor AFX1

All UniProt accessions (1): P98177

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor involved in the regulation of the insulin signaling pathway. Binds to insulin-response elements (IREs) and can activate transcription of IGFBP1. Down-regulates expression of HIF1A and suppresses hypoxia-induced transcriptional activation of HIF1A-modulated genes. Also involved in negative regulation of the cell cycle. Involved in increased proteasome activity in embryonic stem cells (ESCs) by activating expression of PSMD11 in ESCs, leading to enhanced assembly of the 26S proteasome, followed by higher proteasome activity.

Subunit / interactions. Interacts with CREBBP/CBP, CTNNB1, MYOCD, SIRT1, SRF and YWHAZ. Acetylated by CREBBP/CBP and deacetylated by SIRT1. Binding of YWHAZ inhibits DNA-binding. Interacts with USP7; the interaction is enhanced in presence of hydrogen peroxide and occurs independently of TP53. Interacts with NLK, and this inhibits monoubiquitination and transcriptional activity. Interacts with FOXK1; the interaction inhibits MEF2C transactivation activity.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Isoform zeta is most abundant in the liver, kidney, and pancreas.

Post-translational modifications. Acetylation by CREBBP/CBP, which is induced by peroxidase stress, inhibits transcriptional activity. Deacetylation by SIRT1 is NAD-dependent and stimulates transcriptional activity. Phosphorylation by PKB/AKT1 inhibits transcriptional activity and is responsible for cytoplasmic localization. May be phosphorylated at multiple sites by NLK. Monoubiquitinated; monoubiquitination is induced by oxidative stress and reduced by deacetylase inhibitors; results in its relocalization to the nucleus and its increased transcriptional activity. Deubiquitinated by USP7; deubiquitination is induced by oxidative stress; enhances its interaction with USP7 and consequently, deubiquitination; increases its translocation to the cytoplasm and inhibits its transcriptional activity. Hydrogen-peroxide-induced ubiquitination and USP7-mediated deubiquitination have no major effect on its protein stability.

Disease relevance. A chromosomal aberration involving FOXO4 is found in acute leukemias. Translocation t(X;11)(q13;q23) with KMT2A/MLL1. The result is a rogue activator protein.

Isoforms (2)

UniProt ID	Names	Canonical?
P98177-1	1, FOXO4a	yes
P98177-2	Zeta, AFXzeta, FOXO4b

RefSeq proteins (2): NP_001164402, NP_005929* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001766	Fork_head_dom	Domain
IPR030456	TF_fork_head_CS_2	Conserved_site
IPR032067	FOXO-TAD	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR047409	FH_FOXO4	Domain

Pfam: PF00250, PF16676

UniProt features (30 total): sequence conflict 6, helix 5, strand 4, mutagenesis site 3, compositionally biased region 3, modified residue 3, region of interest 2, chain 1, DNA-binding region 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3L2C	X-RAY DIFFRACTION	1.87
1E17	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P98177-F1	55.36	0.14

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 (3): 32, 197, 262

Mutagenesis-validated functional residues (3):

Position	Phenotype
32	abolishes phosphorylation. protein is located mainly in nucleus and shows increased transcriptional activity. increased
197	abolishes phosphorylation. protein is located mainly in nucleus and shows increased transcriptional activity. increased
262	abolishes phosphorylation. no effect on cellular location or transcriptional activity. increased transcriptional and pro

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-198693	AKT phosphorylates targets in the nucleus
R-HSA-5674400	Constitutive Signaling by AKT1 E17K in Cancer
R-HSA-5689880	Ub-specific processing proteases
R-HSA-9614399	Regulation of localization of FOXO transcription factors
R-HSA-9614657	FOXO-mediated transcription of cell death genes
R-HSA-9615017	FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes
R-HSA-9617629	Regulation of FOXO transcriptional activity by acetylation
R-HSA-9617828	FOXO-mediated transcription of cell cycle genes
R-HSA-9733709	Cardiogenesis

MSigDB gene sets: 322 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, TGCGCANK_UNKNOWN, GOBP_RESPONSE_TO_IMMOBILIZATION_STRESS, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, AACYNNNNTTCCS_UNKNOWN, AP4_Q6, GGGTGGRR_PAX4_03, AAAYRNCTG_UNKNOWN, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND

GO Biological Process (20): regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), response to oxidative stress (GO:0006979), mitotic G2 DNA damage checkpoint signaling (GO:0007095), muscle organ development (GO:0007517), negative regulation of cell population proliferation (GO:0008285), insulin receptor signaling pathway (GO:0008286), positive regulation of smooth muscle cell migration (GO:0014911), negative regulation of angiogenesis (GO:0016525), response to nutrient levels (GO:0031667), positive regulation of transcription by RNA polymerase II (GO:0045944), stem cell differentiation (GO:0048863), negative regulation of smooth muscle cell differentiation (GO:0051151), negative regulation of G0 to G1 transition (GO:0070317), response to water-immersion restraint stress (GO:1990785), cell differentiation (GO:0030154), cellular response to oxidative stress (GO:0034599), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of DNA-templated transcription (GO:0045893), protein K48-linked ubiquitination (GO:0070936)

GO Molecular Function (14): 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), nucleic acid binding (GO:0003676), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), beta-catenin binding (GO:0008013), enzyme binding (GO:0019899), identical protein binding (GO:0042802), sequence-specific DNA binding (GO:0043565), DNA-binding transcription factor binding (GO:0140297), sequence-specific double-stranded DNA binding (GO:1990837), promoter-specific chromatin binding (GO:1990841), protein binding (GO:0005515)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear speck (GO:0016607)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
FOXO-mediated transcription	5
PIP3 activates AKT signaling	1
PI3K/AKT Signaling in Cancer	1
Deubiquitination	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
protein binding	3
DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
binding	2
regulation of gene expression	1
regulation of RNA biosynthetic process	1
response to stress	1
mitotic G2 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G2/M transition checkpoint	1
animal organ development	1
muscle structure development	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
smooth muscle cell migration	1
regulation of smooth muscle cell migration	1
positive regulation of cell migration	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
response to stimulus	1
positive regulation of DNA-templated transcription	1
cell differentiation	1
smooth muscle cell differentiation	1
negative regulation of muscle cell differentiation	1
regulation of smooth muscle cell differentiation	1
negative regulation of cell cycle process	1
G0 to G1 transition	1
regulation of G0 to G1 transition	1
response to immobilization stress	1
cellular developmental process	1
response to oxidative stress	1
cellular response to chemical stress	1

Protein interactions and networks

STRING

2224 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXO4	TP53	P04637	992
FOXO4	SIRT1	Q96EB6	891
FOXO4	CTNNB1	P35222	822
FOXO4	EP300	Q09472	807
FOXO4	AKT1	P31749	802
FOXO4	TNPO1	Q92973	779
FOXO4	MYOCD	Q8IZQ8	768
FOXO4	INS	P01308	698
FOXO4	PTEN	P60484	693
FOXO4	FBXO32	Q969P5	690
FOXO4	IGF1	P01343	687
FOXO4	ATXN3	P54252	674
FOXO4	SMPX	Q9UHP9	649
FOXO4	CDKN1B	P46527	645
FOXO4	PDK3	Q15120	616

IntAct

37 interactions, top by confidence:

A	B	Type	Score
SFN	FOXO4	psi-mi:“MI:0915”(physical association)	0.680
FOXO4	SFN	psi-mi:“MI:0915”(physical association)	0.680
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
FOXO4	REL	psi-mi:“MI:0915”(physical association)	0.560
REL	FOXO4	psi-mi:“MI:0915”(physical association)	0.560
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
SIRT1	FOXO4	psi-mi:“MI:0197”(deacetylation reaction)	0.540
FOXO4	SIRT1	psi-mi:“MI:0915”(physical association)	0.540
SMAD4	FOXO4	psi-mi:“MI:0915”(physical association)	0.520
FOXO4	SMAD4	psi-mi:“MI:0915”(physical association)	0.520
FOXO4	FOXO4	psi-mi:“MI:0915”(physical association)	0.500
FOXO4	Foxg1	psi-mi:“MI:0915”(physical association)	0.400
FOXO4	SMAD3	psi-mi:“MI:0915”(physical association)	0.400
FOXO4	H1-2	psi-mi:“MI:0915”(physical association)	0.400
FOXO4	YWHAE	psi-mi:“MI:0915”(physical association)	0.400
FOXO4	Crebbp	psi-mi:“MI:0915”(physical association)	0.400
OGT	FOXO4	psi-mi:“MI:0915”(physical association)	0.400
FOXO4		psi-mi:“MI:0914”(association)	0.350
FOXO1	HOXC13	psi-mi:“MI:0914”(association)	0.350
FOXO1	RB1	psi-mi:“MI:0914”(association)	0.350
FOXO4	FEN1	psi-mi:“MI:0914”(association)	0.350
FOXO6	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
YWHAH	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (55): AKT1 (Affinity Capture-Western), AKT1 (Reconstituted Complex), FOXO4 (Two-hybrid), REL (Two-hybrid), FOXO4 (Biochemical Activity), FOXO4 (Affinity Capture-MS), FEN1 (Affinity Capture-MS), FOXO4 (Affinity Capture-MS), FOXO4 (Affinity Capture-Western), FOXO4 (Affinity Capture-Western), SMAD4 (Affinity Capture-Western), FOXO4 (Reconstituted Complex), XPO1 (Reconstituted Complex), FOXO4 (Proximity Label-MS), FOXO4 (Affinity Capture-Western)

ESM2 similar proteins: A0A0R4IYX6, A1L1F6, A2VCZ5, A3KP40, A5X7A0, A7MB40, A7XYJ6, B7ZS37, E1BE02, E7F888, E9Q2Z1, O35261, O35914, O95402, P59598, P78312, P98177, Q04891, Q4G112, Q53TQ3, Q566I1, Q5W1J6, Q5ZJ69, Q60795, Q66JY2, Q71F56, Q76I79, Q7YR76, Q8AYC2, Q8BHZ4, Q8BZ32, Q8CCJ9, Q8CGI1, Q8IZQ8, Q8K4J6, Q8N365, Q8R4I1, Q8R5I7, Q8VIM5, Q90WM5

Diamond homologs: A0A2Z4LIS9, A3RK74, A3RK75, A4L7N3, A8MYZ6, B3LYS5, B3P0K6, B4G4S8, B4HF64, B4JSC2, B4KBF6, B4MB78, B4NFR1, B4PTD3, E1BPQ1, G3V7R4, O16850, O43524, P0CG31, P23512, P32182, P32183, P32315, P33205, P33206, P35582, P35583, P35584, P55317, P55318, P84961, P98177, Q07342, Q10924, Q12778, Q28EM1, Q298W7, Q3Y598, Q4VUF1, Q63248

SIGNOR signaling

41 interactions.

A	Effect	B	Mechanism
CREB1	“down-regulates activity”	FOXO4	binding
SIRT1	up-regulates	FOXO4	deacetylation
MAPK8	up-regulates	FOXO4	phosphorylation
AKT	down-regulates	FOXO4	phosphorylation
PRKAA1	up-regulates	FOXO4	phosphorylation
JNK	up-regulates	FOXO4	phosphorylation
AKT1	down-regulates	FOXO4	phosphorylation
STK4	up-regulates	FOXO4	phosphorylation
CDK2	down-regulates	FOXO4	phosphorylation
CSNK1A1	down-regulates	FOXO4	phosphorylation
DYRK1A	down-regulates	FOXO4	phosphorylation
AMPK	up-regulates	FOXO4	phosphorylation
AKT2	“down-regulates activity”	FOXO4	phosphorylation
FOXO4	“up-regulates quantity by expression”	FBXO32	“transcriptional regulation”
FOXO4	“up-regulates quantity by expression”	TRIM63	“transcriptional regulation”
TSC22D3	“down-regulates activity”	FOXO4	relocalization
FOXO4	“up-regulates quantity by expression”	IDH1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 23 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	282.9×	6e-17
Activation of BAD and translocation to mitochondria	6	240.4×	2e-12
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	212.1×	4e-12
Activation of BH3-only proteins	6	156.8×	2e-11
FOXO-mediated transcription	7	123.8×	2e-12
RHO GTPases activate PKNs	6	100.2×	4e-10
Intrinsic Pathway for Apoptosis	6	92.5×	6e-10
SARS-CoV-1-host interactions	8	74.0×	2e-12

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	6	31.4×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	48
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

299 predictions. Top by Δscore:

Variant	Effect	Δscore
X:71096979:A:T	donor_gain	1.0000
X:71096979:AAGGT:A	donor_loss	1.0000
X:71096980:AGGT:A	donor_loss	1.0000
X:71096982:G:GA	donor_loss	1.0000
X:71096983:T:A	donor_loss	1.0000
X:71096982:G:GG	donor_gain	0.9900
X:71100679:TCCA:T	acceptor_loss	0.9900
X:71100682:A:AG	acceptor_gain	0.9900
X:71100682:AG:A	acceptor_loss	0.9900
X:71100683:G:GG	acceptor_gain	0.9900
X:71101736:GCCAG:G	donor_gain	0.9900
X:71101737:CCAGG:C	donor_loss	0.9900
X:71101738:CAGGT:C	donor_loss	0.9900
X:71101739:AGGTA:A	donor_loss	0.9900
X:71101741:GTAC:G	donor_loss	0.9900
X:71101742:T:G	donor_loss	0.9900
X:71096974:G:GT	donor_gain	0.9800
X:71096977:GGAAG:G	donor_gain	0.9800
X:71096978:GAAG:G	donor_gain	0.9800
X:71096978:GAAGG:G	donor_gain	0.9800
X:71100683:GA:G	acceptor_gain	0.9800
X:71100683:GAA:G	acceptor_gain	0.9800
X:71100683:GAACT:G	acceptor_gain	0.9800
X:71100673:T:TA	acceptor_gain	0.9700
X:71102071:CCACA:C	acceptor_loss	0.9700
X:71102072:CACA:C	acceptor_loss	0.9700
X:71102073:ACAG:A	acceptor_loss	0.9700
X:71102074:CAGAT:C	acceptor_loss	0.9700
X:71102075:A:AG	acceptor_gain	0.9700
X:71102075:AGATC:A	acceptor_loss	0.9700

AlphaMissense

3267 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:71096823:A:G	N99D	1.000
X:71096829:T:A	W101R	1.000
X:71096829:T:C	W101R	1.000
X:71096830:G:C	W101S	1.000
X:71096831:G:C	W101C	1.000
X:71096831:G:T	W101C	1.000
X:71096832:G:A	G102R	1.000
X:71096832:G:C	G102R	1.000
X:71096833:G:A	G102E	1.000
X:71096833:G:T	G102V	1.000
X:71096844:T:C	Y106H	1.000
X:71096845:A:G	Y106C	1.000
X:71096854:T:A	L109H	1.000
X:71096854:T:C	L109P	1.000
X:71096857:T:A	I110N	1.000
X:71096857:T:C	I110T	1.000
X:71096857:T:G	I110S	1.000
X:71096865:G:C	A113P	1.000
X:71096866:C:A	A113D	1.000
X:71096869:T:A	I114N	1.000
X:71096869:T:G	I114S	1.000
X:71096893:T:C	L122P	1.000
X:71096899:T:A	L124H	1.000
X:71096899:T:C	L124P	1.000
X:71096908:T:A	I127N	1.000
X:71096908:T:G	I127S	1.000
X:71096910:T:C	Y128H	1.000
X:71096916:T:A	W130R	1.000
X:71096916:T:C	W130R	1.000
X:71096918:G:C	W130C	1.000

dbSNP variants (sampled 300 via entrez): RS1000261851 (X:71100813 G>T), RS1000321389 (X:71101549 T>C), RS1000434219 (X:71100560 G>A), RS1000703874 (X:71098914 T>C), RS1001526371 (X:71102178 A>G), RS1001578730 (X:71101595 A>T), RS1002376506 (X:71096390 TA>T), RS1002578584 (X:71103708 A>C), RS1003503613 (X:71102512 A>T), RS1003816903 (X:71095751 C>G,T), RS1004390270 (X:71100267 G>A), RS1005361364 (X:71102268 G>A), RS1006119936 (X:71093966 C>T), RS1006178251 (X:71097438 C>T), RS1006384082 (X:71103823 C>A,G)

Disease associations

OMIM: gene MIM:300033 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): intellectual disability (MONDO:0001071)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cisplatin	increases expression, decreases expression, decreases reaction, decreases response to substance, affects expression (+1 more)	4
Resveratrol	increases phosphorylation, decreases phosphorylation, affects reaction, decreases expression, increases expression (+2 more)	3
Benzo(a)pyrene	decreases phosphorylation, increases reaction, affects activity, affects methylation, decreases methylation (+2 more)	3
bisphenol A	affects cotreatment, increases methylation, increases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Dichlorodiphenyl Dichloroethylene	decreases expression, increases activity	2
Nickel	decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
geraniol	increases expression	1
terbufos	increases methylation	1
trichostatin A	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
aflatoxin B2	increases methylation	1
tamibarotene	increases expression	1
16-hydroxycleroda-3,13(14)-dien-15,16-olide	increases expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	increases reaction, decreases phosphorylation	1
azoxystrobin	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
deguelin	decreases expression	1
2-palmitoylglycerol	increases expression	1
3-nitrobenzanthrone	decreases expression	1
gaillardin	increases expression	1
clothianidin	decreases expression	1
4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide	increases expression	1
asparanin A	increases expression	1
jinfukang	affects cotreatment, increases expression	1
picoxystrobin	decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1326	Karpas-45	Cancer cell line	Male
CVCL_B8GH	Abcam HCT 116 FOXO4 KO	Cancer cell line	Male
CVCL_B8W3	Abcam MCF-7 FOXO4 KO	Cancer cell line	Female
CVCL_B9IR	Abcam A-549 FOXO4 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders