FOXS1

Summary

FOXS1 (forkhead box S1, HGNC:3735) is a protein-coding gene on chromosome 20q11.21, encoding Forkhead box protein S1 (O43638). Transcriptional repressor that suppresses transcription from the FASLG, FOXO3 and FOXO4 promoters.

The forkhead family of transcription factors belongs to the winged helix class of DNA-binding proteins. The protein encoded by this intronless gene contains a forkhead domain and is found predominantly in aorta and kidney. The function of the encoded protein is unknown.

Source: NCBI Gene 2307 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 67 total
• MANE Select transcript: NM_004118

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3735
Approved symbol	FOXS1
Name	forkhead box S1
Location	20q11.21
Locus type	gene with protein product
Status	Approved
Aliases	FREAC10
Ensembl gene	ENSG00000179772
Ensembl biotype	protein_coding
OMIM	602939
Entrez	2307

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000375978

RefSeq mRNA: 1 — MANE Select: NM_004118 NM_004118

CCDS: CCDS13192

Canonical transcript exons

ENST00000375978 — 1 exons

Exon	Start	End
ENSE00001469024	31844303	31845604

Expression profiles

Bgee: expression breadth ubiquitous, 153 present calls, max score 95.12.

FANTOM5 (CAGE): breadth broad, TPM avg 1.5313 / max 140.7162, expressed in 399 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186874	1.3719	380
186875	0.1595	61

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right coronary artery	UBERON:0001625	95.12	gold quality
left coronary artery	UBERON:0001626	89.46	gold quality
coronary artery	UBERON:0001621	89.24	gold quality
ascending aorta	UBERON:0001496	88.67	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.55	gold quality
descending thoracic aorta	UBERON:0002345	88.51	gold quality
popliteal artery	UBERON:0002250	88.50	gold quality
tibial artery	UBERON:0007610	88.50	gold quality
thoracic aorta	UBERON:0001515	88.38	gold quality
aorta	UBERON:0000947	88.33	gold quality
apex of heart	UBERON:0002098	84.64	gold quality
tibial nerve	UBERON:0001323	78.09	gold quality
right atrium auricular region	UBERON:0006631	73.54	gold quality
heart	UBERON:0000948	72.85	gold quality
cardiac atrium	UBERON:0002081	72.85	gold quality
heart left ventricle	UBERON:0002084	72.22	gold quality
metanephros cortex	UBERON:0010533	72.05	gold quality
cardiac ventricle	UBERON:0002082	71.80	gold quality
right lung	UBERON:0002167	71.07	gold quality
dorsal root ganglion	UBERON:0000044	71.05	gold quality
endocervix	UBERON:0000458	69.26	gold quality
tendon of biceps brachii	UBERON:0008188	68.58	gold quality
metanephros	UBERON:0000081	67.89	gold quality
upper lobe of left lung	UBERON:0008952	66.30	gold quality
putamen	UBERON:0001874	65.94	gold quality
endothelial cell	CL:0000115	65.90	silver quality
cortex of kidney	UBERON:0001225	65.77	gold quality
body of uterus	UBERON:0009853	65.69	gold quality
upper lobe of lung	UBERON:0008948	65.17	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	65.15	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-11	yes	20.43
E-ANND-3	no	2.23

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
FASLG	Repression
FOXO3	Repression
FOXO4	Repression

JASPAR motifs

Motif	Name	Family
MA2118.1	FOXS1	FOX

JASPAR matrix evidence (PMIDs): PMID:27965437

miRNA regulators (miRDB)

15 targeting FOXS1, 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-3119	99.92	71.34	2390
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-3160-5P	99.28	69.07	1938
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-4717-3P	99.06	66.34	1072
HSA-MIR-605-5P	98.79	68.24	1161
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-212-5P	96.83	67.43	950
HSA-MIR-1291	96.28	65.89	1224
HSA-MIR-9900	96.06	65.48	557
HSA-MIR-6775-3P	95.76	65.91	982

Literature-anchored findings (GeneRIF, showing 7)

• Study showed that FOXS1 expression is downregulated in gastric cancer tumors and cell lines promoting cell proliferation and metastasis through upregulation of wnt/beta-catenin pathway. (PMID:30500980)
• Forkhead Box S1 mediates epithelial-mesenchymal transition through the Wnt/beta-catenin signaling pathway to regulate colorectal cancer progression. (PMID:35864528)
• ERp44 Regulates the Proliferation, Migration, Invasion, and Apoptosis of Gastric Cancer Cells Via Activation of ER Stress. (PMID:36178559)
• Forkhead Box S1 inhibits the progression of lung squamous cell carcinoma cells by mediating Wnt/beta-catenin pathway. (PMID:36308082)
• FOXS1 promotes prostate cancer progression through the Hedgehog/Gli1 pathway. (PMID:37890593)
• FOXS1 is increased in liver fibrosis and regulates TGFbeta responsiveness and proliferation pathways in human hepatic stellate cells. (PMID:38280429)
• FOXS1 acts as an oncogene and induces EMT through FAK/PI3K/AKT pathway by upregulating HILPDA in prostate cancer. (PMID:38780613)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Foxs1	ENSMUSG00000074676
rattus_norvegicus	Foxs1	ENSRNOG00000090853

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), 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

Forkhead box protein S1 — O43638 (reviewed: O43638)

Alternative names: Forkhead-like 18 protein, Forkhead-related transcription factor 10

All UniProt accessions (1): O43638

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor that suppresses transcription from the FASLG, FOXO3 and FOXO4 promoters. May have a role in the organization of the testicular vasculature.

Subcellular location. Nucleus.

RefSeq proteins (1): NP_004109* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001766	Fork_head_dom	Domain
IPR018122	TF_fork_head_CS_1	Conserved_site
IPR030456	TF_fork_head_CS_2	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR047364	FH_FOXS1	Domain
IPR050211	FOX_domain-containing	Family

Pfam: PF00250

UniProt features (7 total): region of interest 2, compositionally biased region 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-O43638-F1	64.43	0.25

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 95 (showing top): CREL_01, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_GROWTH, CAGCTG_AP4_Q5, MODULE_503, GOBP_NEUROMUSCULAR_PROCESS_CONTROLLING_BALANCE, NFKB_Q6, GOBP_REGULATION_OF_MULTICELLULAR_ORGANISM_GROWTH, MODULE_195, GOBP_MULTICELLULAR_ORGANISM_GROWTH, GOBP_NEGATIVE_REGULATION_OF_MOLECULAR_FUNCTION, GGGNNTTTCC_NFKB_Q6_01, GOBP_POSITIVE_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_POSITIVE_REGULATION_OF_GROWTH, GOBP_POSITIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS

GO Biological Process (10): blood vessel development (GO:0001568), regulation of transcription by RNA polymerase II (GO:0006357), anatomical structure morphogenesis (GO:0009653), cell differentiation (GO:0030154), positive regulation of multicellular organism growth (GO:0040018), obsolete negative regulation of DNA-binding transcription factor activity (GO:0043433), negative regulation of DNA-templated transcription (GO:0045892), neuromuscular process controlling balance (GO:0050885), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (6): 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 (GO:0003677), DNA-binding transcription factor activity (GO:0003700), 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
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
anatomical structure development	2
transcription by RNA polymerase II	2
DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
vasculature development	1
developmental process	1
cellular developmental process	1
multicellular organism growth	1
regulation of multicellular organism growth	1
positive regulation of developmental growth	1
positive regulation of multicellular organismal process	1
negative regulation of RNA biosynthetic process	1
musculoskeletal movement	1
neuromuscular process	1
negative regulation of 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
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
DNA binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1320 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXS1	MYLK2	Q9H1R3	560
FOXS1	C1orf198	Q9H425	480
FOXS1	DLX2	Q07687	470
FOXS1	SOX4	Q06945	461
FOXS1	BATF	Q16520	438
FOXS1	ASCL1	P50553	432
FOXS1	JUN	P05412	421
FOXS1	LGALSL	Q3ZCW2	400
FOXS1	CCM2L	Q9NUG4	398
FOXS1	SOX17	Q9H6I2	370
FOXS1	ZNF564	Q8TBZ8	360
FOXS1	DUSP15	Q9H1R2	354
FOXS1	TFCP2L1	Q9NZI6	353
FOXS1	FOXR2	Q6PJQ5	351
FOXS1	LAMP5	Q9UJQ1	324
FOXS1	CST2	P09228	324

IntAct

9 interactions, top by confidence:

A	B	Type	Score
RBPMS	FOXS1	psi-mi:“MI:0915”(physical association)	0.550
FOXS1	RBPMS	psi-mi:“MI:0915”(physical association)	0.550
BMI1	FOXS1	psi-mi:“MI:0915”(physical association)	0.370
FOXS1	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXS1	PPP2R1B	psi-mi:“MI:0914”(association)	0.350
FOXS1	GAPDHS	psi-mi:“MI:0914”(association)	0.350

BioGRID (97): PPP2R1B (Affinity Capture-MS), PPP2R2D (Affinity Capture-MS), ACOX1 (Affinity Capture-MS), KBTBD6 (Affinity Capture-MS), MIPEP (Affinity Capture-MS), PPP2CA (Affinity Capture-MS), RBPMS (Two-hybrid), HOXD13 (Affinity Capture-MS), FOXC1 (Affinity Capture-MS), AKAP8 (Affinity Capture-MS), RALY (Affinity Capture-MS), SATB2 (Affinity Capture-MS), UQCRFS1 (Affinity Capture-MS), ADAR (Affinity Capture-MS), GTF3C5 (Affinity Capture-MS)

ESM2 similar proteins: A0A1W2PQ73, A1YF16, A1YG93, A2RU54, A5PKG8, O02786, O14813, O15353, O35602, O43638, O57601, P13297, P19419, P28360, P35548, P41969, P42580, P43687, P49640, P50223, P50548, P52946, P52950, P63156, P63157, P70459, P78413, Q03358, Q14549, Q2VL78, Q2VL79, Q2VL82, Q2VL83, Q2VL84, Q2VL85, Q2VL86, Q2VL87, Q2VL88, Q5NSW5, Q61575

Diamond homologs: A0A078BQN7, A0A1W2PRP0, A0A8V0YY16, A1L1S5, A3KNJ3, A8MTJ6, A8XJN7, B5RHS5, D3Z120, F1R8Z9, O00358, O17617, O43638, O54743, O60129, O88470, P32027, P32028, P32030, P32315, P42128, P55316, P56260, P58012, P79772, P85037, P91278, Q00939, Q01167, Q02360, Q12946, Q12947, Q12948, Q12950, Q12951, Q12952, Q13461, Q19802, Q1A1A1, Q1A1A2

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
FOXS1	“down-regulates quantity by repression”	FOXO3	“transcriptional regulation”
FOXS1	“down-regulates quantity by repression”	FOXO4	“transcriptional regulation”
FOXS1	“down-regulates quantity by repression”	FASLG	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	61
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

153 predictions. Top by Δscore:

Variant	Effect	Δscore
20:31845052:AGGC:A	donor_gain	0.7900
20:31845092:G:GA	donor_gain	0.7000
20:31845052:AGG:A	donor_gain	0.6700
20:31845096:G:A	donor_gain	0.5800
20:31844818:GATTC:G	acceptor_gain	0.5400
20:31844634:GCCAC:G	acceptor_loss	0.5000
20:31844636:CAC:C	acceptor_loss	0.5000
20:31844637:ACCTG:A	acceptor_loss	0.5000
20:31844638:CCTGC:C	acceptor_loss	0.5000
20:31844639:C:G	acceptor_loss	0.5000
20:31844640:T:G	acceptor_loss	0.5000
20:31844653:T:TA	donor_gain	0.5000
20:31844748:AAGG:A	donor_gain	0.5000
20:31844641:G:C	acceptor_loss	0.4800
20:31844557:A:C	donor_gain	0.4700
20:31844931:C:A	donor_gain	0.4700
20:31845124:T:TA	donor_gain	0.4700
20:31844648:A:T	acceptor_loss	0.4600
20:31844802:G:C	donor_gain	0.4500
20:31845118:C:CA	donor_gain	0.4500
20:31844647:CAGGG:C	acceptor_loss	0.4400
20:31845477:G:C	donor_gain	0.4400
20:31844620:C:A	donor_gain	0.4300
20:31844640:TGCA:T	donor_gain	0.4300
20:31844643:A:T	acceptor_loss	0.4300
20:31844862:AG:A	donor_gain	0.4300
20:31844529:C:CC	acceptor_gain	0.4200
20:31844635:C:CT	donor_gain	0.4200
20:31845052:AGGCC:A	donor_gain	0.4200
20:31844528:ACT:A	acceptor_gain	0.4100

AlphaMissense

2116 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:31845267:C:A	W92C	1.000
20:31845267:C:G	W92C	1.000
20:31845269:A:G	W92R	1.000
20:31845269:A:T	W92R	1.000
20:31845315:A:C	F76L	1.000
20:31845315:A:T	F76L	1.000
20:31845316:A:C	F76C	1.000
20:31845316:A:G	F76S	1.000
20:31845317:A:G	F76L	1.000
20:31845334:A:G	L70P	1.000
20:31845334:A:T	L70Q	1.000
20:31845339:G:C	H68Q	1.000
20:31845339:G:T	H68Q	1.000
20:31845341:G:C	H68D	1.000
20:31845346:A:T	I66N	1.000
20:31845357:C:A	W62C	1.000
20:31845357:C:G	W62C	1.000
20:31845359:A:G	W62R	1.000
20:31845359:A:T	W62R	1.000
20:31845387:G:C	F52L	1.000
20:31845387:G:T	F52L	1.000
20:31845389:A:G	F52L	1.000
20:31845237:A:C	F102L	0.999
20:31845237:A:T	F102L	0.999
20:31845238:A:C	F102C	0.999
20:31845239:A:G	F102L	0.999
20:31845268:C:G	W92S	0.999
20:31845309:C:A	K78N	0.999
20:31845309:C:G	K78N	0.999
20:31845317:A:C	F76V	0.999

dbSNP variants (sampled 300 via entrez): RS1002921569 (20:31847495 C>T), RS1003232111 (20:31846041 G>A), RS1003255487 (20:31846278 A>C), RS1003307837 (20:31846072 G>A), RS1003308306 (20:31845069 C>A,T), RS1003881768 (20:31845739 G>A,C), RS1006221344 (20:31844386 C>A,T), RS1006581850 (20:31844617 C>G,T), RS1006889668 (20:31846573 C>T), RS1006925374 (20:31846802 C>G), RS1007248269 (20:31846850 C>A,T), RS1008087594 (20:31844202 A>C,G), RS1010062428 (20:31844023 A>C), RS1010164630 (20:31844168 A>G), RS1010425783 (20:31844229 C>G)

Disease associations

OMIM: gene MIM:602939 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003030_10	Oppositional defiant disorder dimensions in attention-deficit hyperactivity disorder	3.000000e-06
GCST003030_9	Oppositional defiant disorder dimensions in attention-deficit hyperactivity disorder	4.000000e-06
GCST004630_71	Mean corpuscular hemoglobin	2.000000e-17
GCST010703_295	Brain morphology (MOSTest)	1.000000e-14

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007679	oppositional defiant disorder measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
monobutyl phthalate	increases methylation	1
nutlin 3	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Oxygen	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases methylation	1
1-Methyl-4-phenylpyridinium	increases expression	1
Aflatoxin B1	decreases methylation	1
Gold Compounds	decreases expression, increases methylation	1
Cadmium Chloride	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A2D6	SEES3-1V human FOXS1, clone1	Embryonic stem cell	Male
CVCL_A2D7	SEES3-1V human FOXS1, clone2	Embryonic stem cell	Male
CVCL_A2D8	SEES3-1V human FOXS1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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