ONECUT3

Summary

ONECUT3 (one cut homeobox 3, HGNC:13399) is a protein-coding gene on chromosome 19p13.3, encoding One cut domain family member 3 (O60422). Transcriptional activator.

Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in chromatin. Predicted to be part of transcription regulator complex. Predicted to be active in nucleus.

Source: NCBI Gene 390874 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 109 total
• MANE Select transcript: NM_001080488

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13399
Approved symbol	ONECUT3
Name	one cut homeobox 3
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000205922
Ensembl biotype	protein_coding
OMIM	611294
Entrez	390874

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000382349

RefSeq mRNA: 1 — MANE Select: NM_001080488 NM_001080488

CCDS: CCDS45900

Canonical transcript exons

ENST00000382349 — 2 exons

Exon	Start	End
ENSE00001491805	1775153	1780988
ENSE00001535118	1753506	1754854

Expression profiles

Bgee: expression breadth broad, 24 present calls, max score 87.94.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3804 / max 57.4169, expressed in 78 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172998	0.3296	75
172999	0.0265	14
173000	0.0221	12
172997	0.0023	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	87.94	gold quality
pylorus	UBERON:0001166	74.34	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.43	gold quality
tendon of biceps brachii	UBERON:0008188	69.25	silver quality
trabecular bone tissue	UBERON:0002483	68.94	gold quality
oocyte	CL:0000023	66.62	gold quality
gingival epithelium	UBERON:0001949	66.13	gold quality
jejunal mucosa	UBERON:0000399	65.99	gold quality
jejunum	UBERON:0002115	64.14	gold quality
parotid gland	UBERON:0001831	63.95	gold quality
secondary oocyte	CL:0000655	63.83	gold quality
gingiva	UBERON:0001828	63.80	gold quality
palpebral conjunctiva	UBERON:0001812	63.51	gold quality
nipple	UBERON:0002030	63.03	gold quality
amniotic fluid	UBERON:0000173	63.00	gold quality
tibia	UBERON:0000979	62.77	gold quality
myocardium	UBERON:0002349	62.76	gold quality
parietal pleura	UBERON:0002400	62.53	gold quality
visceral pleura	UBERON:0002401	62.42	gold quality
ventral tegmental area	UBERON:0002691	62.14	gold quality
saphenous vein	UBERON:0007318	62.14	gold quality
pericardium	UBERON:0002407	61.94	gold quality
germinal epithelium of ovary	UBERON:0001304	61.89	gold quality
synovial joint	UBERON:0002217	61.89	gold quality
inferior vagus X ganglion	UBERON:0005363	61.79	gold quality
mucosa of sigmoid colon	UBERON:0004993	61.61	gold quality
subthalamic nucleus	UBERON:0001906	61.55	gold quality
thymus	UBERON:0002370	61.55	gold quality
cardia of stomach	UBERON:0001162	61.50	gold quality
colonic mucosa	UBERON:0000317	61.41	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9154	yes	440.99
E-GEOD-137537	yes	5.56
E-ANND-3	no	2.29

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
ONECUT1	Activation

JASPAR motifs

Motif	Name	Family
MA0757.1	ONECUT3	HD-CUT
MA0757.2	ONECUT3	HD-CUT

JASPAR matrix evidence (PMIDs): PMID:8887657

Upstream regulators (CollecTRI, top): ONECUT1, TCF23

Literature-anchored findings (GeneRIF, showing 4)

• In conclusion, CD44 and Oct3/4 overexpression may imply malignant transformation of pancreatic ducts and could help pathologists make a more accurate diagnosis and decision on clear surgical margins. (PMID:28464601)
• Data show that chromatin regions that contain the ONECUT motif were in- or lowly accessible in fibroblasts and became accessible after the overexpression of ONECUT1, ONECUT2 or ONECUT3. (PMID:31049588)
• Identification of ONECUT3 as a stemness-related transcription factor regulating NK cell-mediated immune evasion in pancreatic cancer. (PMID:37875589)
• Ectopic expression of the transcription factor ONECUT3 drives a complex karyotype in myelodysplastic syndromes. (PMID:38386414)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	onecut3a	ENSDARG00000056395
danio_rerio	onecut3b	ENSDARG00000091059
mus_musculus	Onecut3	ENSMUSG00000045518
rattus_norvegicus	Onecut3	ENSRNOG00000068848
drosophila_melanogaster	onecut	FBGN0028996
caenorhabditis_elegans		WBGENE00000444
caenorhabditis_elegans		WBGENE00000459
caenorhabditis_elegans		WBGENE00000460
caenorhabditis_elegans		WBGENE00015934
caenorhabditis_elegans		WBGENE00017538

Paralogs (2): ONECUT2 (ENSG00000119547), ONECUT1 (ENSG00000169856)

Protein

Protein identifiers

One cut domain family member 3 — O60422 (reviewed: O60422)

Alternative names: One cut homeobox 3, Transcription factor ONECUT-3

All UniProt accessions (1): O60422

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator. Binds the consensus DNA sequence 5’-DHWATTGAYTWWD-3’ on a variety of gene promoters such as those of HNF3B and TTR.

Subcellular location. Nucleus.

Similarity. Belongs to the CUT homeobox family.

RefSeq proteins (1): NP_001073957* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR003350	CUT_dom	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR010982	Lambda_DNA-bd_dom_sf	Homologous_superfamily
IPR051649	CUT_Homeobox	Family

Pfam: PF00046, PF02376

UniProt features (11 total): compositionally biased region 4, region of interest 4, DNA-binding region 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60422-F1	59.72	0.28

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-210744	Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells
R-HSA-210747	Regulation of gene expression in early pancreatic precursor cells

MSigDB gene sets: 39 (showing top): GOCC_TRANSCRIPTION_REGULATOR_COMPLEX, REACTOME_REGULATION_OF_BETA_CELL_DEVELOPMENT, chr19p13, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, MEISSNER_BRAIN_HCP_WITH_H3K27ME3, MEISSNER_NPC_HCP_WITH_H3K4ME2_AND_H3K27ME3, MIKKELSEN_MCV6_HCP_WITH_H3K27ME3, MIKKELSEN_NPC_HCP_WITH_H3K27ME3, MIKKELSEN_MEF_HCP_WITH_H3K27ME3, GOBP_POSITIVE_REGULATION_OF_TRANSCRIPTION_BY_RNA_POLYMERASE_II, GOMF_DNA_BINDING_TRANSCRIPTION_ACTIVATOR_ACTIVITY, REACTOME_REGULATION_OF_GENE_EXPRESSION_IN_LATE_STAGE_BRANCHING_MORPHOGENESIS_PANCREATIC_BUD_PRECURSOR_CELLS, REACTOME_REGULATION_OF_GENE_EXPRESSION_IN_EARLY_PANCREATIC_PRECURSOR_CELLS, GOMF_TRANSCRIPTION_REGULATOR_ACTIVITY, GSE13738_RESTING_VS_BYSTANDER_ACTIVATED_CD4_TCELL_UP

GO Biological Process (2): regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (8): 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), sequence-specific double-stranded DNA binding (GO:1990837), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Regulation of beta-cell development	2

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 DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
positive regulation of DNA-templated transcription	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
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
transcription regulator activity	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1
protein-containing complex	1

Protein interactions and networks

STRING

486 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ONECUT3	FOXA2	Q9Y261	648
ONECUT3	TCF15	Q12870	590
ONECUT3	TTR	P02766	560
ONECUT3	DNAJB7	Q7Z6W7	542
ONECUT3	MAU2	Q9Y6X3	420
ONECUT3	SATB2	Q9UPW6	379
ONECUT3	ENY2	Q9NPA8	378
ONECUT3	CTCFL	Q8NI51	364
ONECUT3	ATOSA	Q32MH5	340
ONECUT3	ZNF766	Q5HY98	335
ONECUT3	LGALS1	P09382	325
ONECUT3	FECH	P22830	314
ONECUT3	VSX2	P58304	313
ONECUT3	ZNF784	Q8NCA9	312
ONECUT3	ZNF133	P52736	308

IntAct

16 interactions, top by confidence:

A	B	Type	Score
	ONECUT3	psi-mi:“MI:0915”(physical association)	0.560
ONECUT3	CIB1	psi-mi:“MI:0915”(physical association)	0.560
NCK2	ONECUT3	psi-mi:“MI:0915”(physical association)	0.560
ONECUT3	ZMYND12	psi-mi:“MI:0915”(physical association)	0.560
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
CACNA1C	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
ONECUT3		psi-mi:“MI:0915”(physical association)	0.000
ONECUT3	ZMYND12	psi-mi:“MI:0915”(physical association)	0.000
ONECUT3	CIB1	psi-mi:“MI:0915”(physical association)	0.000
NCK2	ONECUT3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): ONECUT3 (Two-hybrid), ONECUT3 (Two-hybrid), ONECUT3 (Two-hybrid), ONECUT3 (Two-hybrid), NCL (Cross-Linking-MS (XL-MS)), ONECUT3 (Affinity Capture-MS), ONECUT3 (Affinity Capture-MS), SCAMP3 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: O08755, O16011, O43312, O60422, O77638, O88532, O88942, O95948, P0CL69, P17544, P54288, P70512, P98201, Q01826, Q02930, Q08289, Q08DV5, Q13469, Q3UR85, Q5R9C9, Q5REX3, Q5VTB9, Q60591, Q60611, Q6NT76, Q6P1E1, Q6P9S0, Q6PDX6, Q6UFS5, Q6UUV9, Q6XBJ3, Q765P7, Q7TMA2, Q8BIE6, Q8BJA3, Q8C0V0, Q8CIE2, Q8HXD5, Q8K557, Q8NF64

Diamond homologs: O08755, O14529, O60422, O95948, P70298, P70512, Q04650, Q19720, Q22811, Q22812, Q6XBJ3, Q8K557, Q8TE12, Q9BL02, Q9JKU8, Q9NJB5, Q9UBC0, P39880, P39881, P53565, P10180, O42115, Q8IA98

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	105
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

987 predictions. Top by Δscore:

Variant	Effect	Δscore
19:1763975:GT:G	donor_gain	0.9900
19:1775440:GCC:G	donor_gain	0.9800
19:1754802:G:GT	donor_gain	0.9700
19:1754852:CAG:C	donor_loss	0.9700
19:1754853:AGGTA:A	donor_loss	0.9700
19:1754854:GGTAG:G	donor_loss	0.9700
19:1754855:GTAG:G	donor_loss	0.9700
19:1754856:T:G	donor_loss	0.9700
19:1763973:GAGT:G	donor_gain	0.9700
19:1775066:G:A	acceptor_gain	0.9600
19:1754796:G:GT	donor_gain	0.9500
19:1775065:C:A	acceptor_gain	0.9500
19:1776544:G:GT	donor_gain	0.9300
19:1758104:G:T	donor_gain	0.9200
19:1775381:C:G	donor_gain	0.9200
19:1776545:A:T	donor_gain	0.9200
19:1760397:TC:T	donor_gain	0.9100
19:1773659:TCACA:T	donor_gain	0.9100
19:1754852:C:T	donor_gain	0.8800
19:1758745:G:GG	donor_gain	0.8800
19:1763977:G:GG	donor_gain	0.8800
19:1775060:T:G	acceptor_gain	0.8800
19:1775093:C:CA	acceptor_gain	0.8700
19:1763860:G:GA	donor_gain	0.8600
19:1775380:GC:G	donor_gain	0.8600
19:1758103:G:GT	donor_gain	0.8500
19:1767197:C:T	donor_gain	0.8500
19:1754995:G:GT	donor_gain	0.8400
19:1755045:G:GT	donor_gain	0.8400
19:1773739:A:T	donor_gain	0.8400

AlphaMissense

3139 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:1754630:C:T	T323I	1.000
19:1754642:C:A	A327E	1.000
19:1754648:G:C	R329P	1.000
19:1754650:A:T	I330F	1.000
19:1754651:T:A	I330N	1.000
19:1754651:T:G	I330S	1.000
19:1754656:G:C	A332P	1.000
19:1754659:G:A	E333K	1.000
19:1754663:T:A	L334Q	1.000
19:1754663:T:C	L334P	1.000
19:1754663:T:G	L334R	1.000
19:1754667:G:C	K335N	1.000
19:1754667:G:T	K335N	1.000
19:1754671:T:G	Y337D	1.000
19:1754674:A:C	S338R	1.000
19:1754676:C:A	S338R	1.000
19:1754676:C:G	S338R	1.000
19:1754678:T:A	I339N	1.000
19:1754678:T:C	I339T	1.000
19:1754678:T:G	I339S	1.000
19:1754680:C:A	P340T	1.000
19:1754681:C:A	P340Q	1.000
19:1754681:C:G	P340R	1.000
19:1754681:C:T	P340L	1.000
19:1754685:G:C	Q341H	1.000
19:1754685:G:T	Q341H	1.000
19:1754690:T:A	I343N	1.000
19:1754692:T:A	F344I	1.000
19:1754692:T:C	F344L	1.000
19:1754692:T:G	F344V	1.000

dbSNP variants (sampled 300 via entrez): RS1000003978 (19:1760433 G>A), RS1000089348 (19:1780183 C>A,G,T), RS1000117398 (19:1754076 C>A,T), RS1000139703 (19:1776045 C>G), RS1000295011 (19:1766341 CG>C), RS1000505109 (19:1777048 G>A,C), RS1000521129 (19:1779798 G>A), RS1000563746 (19:1775408 G>A,C), RS1000571978 (19:1779493 C>A,G,T), RS1000770808 (19:1757830 G>A), RS1000803193 (19:1774438 A>C), RS1000881443 (19:1764222 C>G), RS1000961526 (19:1769649 A>G), RS1001017782 (19:1774946 T>C), RS1001131783 (19:1774580 T>C)

Disease associations

OMIM: gene MIM:611294 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sotorasib	affects cotreatment, decreases expression	1
bisphenol A	decreases methylation	1
sodium arsenite	decreases expression	1
aflatoxin B2	decreases methylation	1
2-palmitoylglycerol	increases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation	1
Copper	affects cotreatment, decreases expression	1
Endosulfan	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Aflatoxin B1	decreases methylation	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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