RUNX3

Summary

RUNX3 (RUNX family transcription factor 3, HGNC:10473) is a protein-coding gene on chromosome 1p36.11, encoding Runt-related transcription factor 3 (Q13761). Forms the heterodimeric complex core-binding factor (CBF) with CBFB.

This gene encodes a member of the runt domain-containing family of transcription factors. A heterodimer of this protein and a beta subunit forms a complex that binds to the core DNA sequence 5’-PYGPYGGT-3’ found in a number of enhancers and promoters, and can either activate or suppress transcription. It also interacts with other transcription factors. It functions as a tumor suppressor, and the gene is frequently deleted or transcriptionally silenced in cancer. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 864 — RefSeq curated summary.

At a glance

• GWAS associations: 39
• Clinical variants (ClinVar): 47 total
• Transcription factor: yes — 75 downstream targets (CollecTRI)
• MANE Select transcript: NM_004350

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10473
Approved symbol	RUNX3
Name	RUNX family transcription factor 3
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	AML2, PEBP2A3
Ensembl gene	ENSG00000020633
Ensembl biotype	protein_coding
OMIM	600210
Entrez	864

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000308873, ENST00000338888, ENST00000399916, ENST00000479341, ENST00000496967

RefSeq mRNA: 3 — MANE Select: NM_004350 NM_001031680, NM_001320672, NM_004350

CCDS: CCDS257, CCDS30633

Canonical transcript exons

ENST00000308873 — 5 exons

Exon	Start	End
ENSE00001540761	24899511	24902666
ENSE00001923902	24929587	24930276
ENSE00003584679	24907259	24907417
ENSE00003599289	24927574	24927730
ENSE00003656276	24919240	24919344

Expression profiles

Bgee: expression breadth ubiquitous, 220 present calls, max score 98.10.

FANTOM5 (CAGE): breadth broad, TPM avg 20.1970 / max 856.7357, expressed in 788 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11068	13.2691	679
11071	3.4368	306
11067	0.9901	329
11062	0.5795	193
11072	0.4283	176
11065	0.3382	171
11069	0.2781	72
11073	0.2560	153
11061	0.2241	102
11074	0.1357	95

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.10	gold quality
buccal mucosa cell	CL:0002336	95.53	gold quality
lymph node	UBERON:0000029	93.68	gold quality
blood	UBERON:0000178	92.77	gold quality
vermiform appendix	UBERON:0001154	92.57	gold quality
caecum	UBERON:0001153	90.22	gold quality
leukocyte	CL:0000738	90.12	gold quality
mononuclear cell	CL:0000842	89.47	gold quality
tibia	UBERON:0000979	89.37	gold quality
spleen	UBERON:0002106	89.32	gold quality
monocyte	CL:0000576	89.25	gold quality
bone marrow cell	CL:0002092	89.25	gold quality
nipple	UBERON:0002030	88.47	gold quality
pylorus	UBERON:0001166	86.64	gold quality
parotid gland	UBERON:0001831	85.93	silver quality
bone marrow	UBERON:0002371	85.11	gold quality
vena cava	UBERON:0004087	84.13	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	84.05	gold quality
upper arm skin	UBERON:0004263	83.98	gold quality
epithelium of nasopharynx	UBERON:0001951	83.59	gold quality
thymus	UBERON:0002370	83.53	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.70	gold quality
palpebral conjunctiva	UBERON:0001812	82.39	gold quality
trachea	UBERON:0003126	82.16	gold quality
periodontal ligament	UBERON:0008266	81.88	gold quality
nasal cavity epithelium	UBERON:0005384	81.85	gold quality
tonsil	UBERON:0002372	81.81	gold quality
lateral nuclear group of thalamus	UBERON:0002736	81.31	silver quality
nasal cavity mucosa	UBERON:0001826	81.20	gold quality
trabecular bone tissue	UBERON:0002483	81.17	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-HCAD-36	yes	1148.40
E-MTAB-6701	yes	88.86
E-CURD-122	yes	40.09
E-MTAB-10287	yes	32.67
E-GEOD-135922	yes	32.23
E-MTAB-6678	yes	24.49
E-ANND-3	yes	20.21
E-CURD-114	yes	20.04
E-MTAB-9067	yes	3.80
E-GEOD-149689	no	689.21
E-GEOD-100618	no	166.23
E-CURD-112	no	3.57

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

75 targets.

Target	Regulation
ABCB1	Unknown
ABCC1	Unknown
ACAN	Unknown
ADAM2
AGTRAP	Unknown
AKT1	Unknown
AXIN2	Repression
BCL2	Repression
BCL2L11	Unknown
BIRC5	Unknown
CAPN10	Activation
CASP2	Activation
CASP3	Activation
CASP7	Activation
CASP8	Activation
CCND1	Repression
CCR7	Repression
CD36	Repression
CD4	Repression
CD6	Unknown
CD79A	Activation
CD8A	Unknown
CDKN1A	Activation
CFLAR	Repression
CHUK	Repression
CLDN7	Activation
CLEC4G	Activation
CXCL8	Repression
DNASE1	Activation
ELANE	Activation

JASPAR motifs

Motif	Name	Family
MA0684.1	RUNX3	Runt-related factors
MA0684.2	RUNX3	Runt-related factors
MA0684.3	RUNX3	Runt-related factors

JASPAR matrix evidence (PMIDs): PMID:20483917, PMID:20378718

Upstream regulators (CollecTRI, top): CBFB, DNMT1, EHMT2, ETS1, EZH2, FOXC1, GATA3, GLI1, HDAC1, IRF4, MYC, RUNX1, SPI1, STAT1

miRNA regulators (miRDB)

98 targeting RUNX3, 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-656-3P	100.00	72.15	2788
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-6077	99.99	68.04	2299
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-4487	99.96	64.58	1252
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-4731-5P	99.89	67.23	2537

Literature-anchored findings (GeneRIF, showing 40)

• RUNX3 methylation is associated with gastric cancers (PMID:12824905)
• RUNX3/AML-2 binding to the CD11a promoter correlates with increased RUNX3/AML-2 protein levels and enhanced CD11a/CD18 cell surface expression (PMID:12855590)
• These results strongly suggest that RUNX3 is one of the tumor suppressors involved in the pathogenesis of testicular yolk sac tumors in infants. (PMID:12875960)
• results suggest that loss of RUNX3 expression by DNA hypermethylation is frequently associated with the evolution of lung cancer (PMID:14715269)
• Inactivation of RUNX3 gene through allelic loss and promoter hypermethylation might be one of the major mechanisms in hepatocellular carcinogenesis. (PMID:14760761)
• Our results overall suggest that transcriptional inactivation of RUNX3 by promoter hypermethylation may participate in the stomach carcinogenesis. (PMID:15051926)
• Data show that RUNX3 is a target of the acetyltransferase activity of p300 acetyltransferase. (PMID:15138260)
• Transcriptional repression of RUNX3 is caused by promoter hypermethylation of the RUNX3 CpG island in colorectal cancer cell lines. (PMID:15273736)
• Expression of RUNX3 is down regulated in a significant portion of gastric cancer cases; may be involved in gastric carcinogenesis (PMID:15386419)
• RUNX3 regulates RUNX1 expression in human B lymphoid cell lines. (PMID:15688019)
• The percentage of CD4-8+ cells increases and the percentage of CD4+8+ and CD4+8- cells simultaneously decreases in the Runx3-transgenic thymus. Thus, Runx3 can drive thymocytes to select the CD4-8+ lineage. (PMID:15728469)
• an inhibitory element was identified in the KIR2DL4 promoter and an activating element was found in the KIR3DL3 promoter; AML-2 acts as a repressor of expression of both KIR2DL4 and KIR3DL3 in mature NK cells (PMID:15778373)
• Hypermethylation of RUNX3 may play an important role in early events of hepatocarcinogenesis. (PMID:15780064)
• The expression of RUNX3 protein in lung AC might play a pivotal role in tumor progression and patients’ survival (PMID:15819721)
• Hypermethylation of p16, RUNX3, and HPP1 in Barreett exophagus may represent independent risk factors for the progression of Barrett esophagus to esophageal cancer. (PMID:15824739)
• RUNX3 aberrant methylation might play an important role in colorectal cancers, especially in poorly-differentiated colorectal cancers. (PMID:16080503)
• findings refute a role for RUNX3 as a tumor-suppressor gene in early-onset gastric carcinogenesis (PMID:16091737)
• RUNX3 is required for the TGF-beta-dependent induction of p21 expression in stomach epithelial cells. (PMID:16135801)
• RUNX3 was found to be inactive in 82% of gastric cancers through either gene silencing or protein mislocalization to the cytoplasm. (PMID:16140942)
• RUNX3 is downregulated by hemizygous deletion at 1p36 in human lung cancer cell lines (PMID:16142337)
• Promoter hypermethylation of RUNX3 gene may occur as an early event in the development of hepatocellular carcinoma (HCC) and that methylation may be a major mechanism for inactivation of RUNX3 gene in HCC. (PMID:16155404)
• RUNX3 gene plays an important role in the pathogenesis of lung cancer, and aberrant methylation is an important mechanism of inactivation of the RUNX3 gene in lung AdC. (PMID:16328045)
• detection of hypermethylation at multiple regions within the RUNX3 CpG island may be useful in the diagnosis and risk assessment of gastric cancer (PMID:16367921)
• RUNX3 cooperates with FoxO3a/FKHRL1 to participate in the induction of apoptosis by activating Bim (PMID:16373335)
• KAP5 gene expression in human hair follicles is regulated by Runx1 (PMID:16442267)
• The expression of RUNX3 was studied in esophageal mucosa and squamous cell carcinoma as well as in comparison with clinicopathological profiles. (PMID:16582583)
• analysis of how the RUNX3 gene induces apoptosis in gastric cancer (PMID:16627973)
• results suggest that mammalian RUNX family transcription factors are novel binding partners and substrates for the Pim-1 kinase, which may be able to regulate their activities during normal hematopoiesis as well as in leukemogenesis (PMID:16684349)
• results indicate that although the deregulation of Wnt signalling could contribute to the pathogenesis of a subset of basal cell carcinomas (BCC), RUNX3 appears to be a universal downstream mediator of a constitutively active Shh pathway in BCC (PMID:16767156)
• In breast tumors, hypermethylation of RUNX3 was observed in 23 of 44 cases. Mislocalization of the protein, with or without methylation, seems to account for RUNX3 inactivation in the vast majority of the tumors. (PMID:16818622)
• Runx3 impairs the activity of the proximal regulatory region of the CD36 gene in myeloid cells through in vitro recognition of two functional RUNX-binding elements. (PMID:16887969)
• Methylation rates (MR) in four of the cancer cell lines that lost RUNX3 mRNA ranged from 99.0% to 99.7% (mean, 99.4%), whereas MR in the remaining cell line that expressed RUNX3 mRNA was 0.6%. (PMID:16984612)
• transcription factor Runx3 is induced in T helper type 1 cells in a T-bet-dependent manner, and that both transcription factors T-bet and Runx3 are required for maximal production of interferon-gamma and silencing of the gene encoding IL-4 in Th1 cells (PMID:17195845)
• RUNX3 protein expression in tumor tissues was significantly higher than that in non-tumor tissues, and was correlated with tumor differentiation. (PMID:17380460)
• RUNX3 silencing promotes radioresistance in esophageal cancers (PMID:17384682)
• RUNX3 is involved in TGF-beta-induced expression of p21 and the resulting induction of TGF-beta-dependent G(1) arrest. (PMID:17470130)
• The present data suggest that TGF-beta, LMO1, possibly RUNX3, and GSDM form a regulatory pathway for directing the pit cells to apoptosis. (PMID:17471240)
• Runx3 determines TrkC positive sensory neuron identities through the transcriptional repression of TrkB when Trk-BTrkC double positive neurons differentiate into TrkC single positive neurons. (PMID:17584746)
• Important target of DNA methylation in the evolution of microsatellite instability in gastric cancer. (PMID:17591800)
• A panel of markers including at least RUNX3, CACNA1G, IGF2, and MLH1 can serve as a sensitive and specific marker panel for CIMP(Cpg island methylator phenotype)-high. (PMID:17591929)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	runx3	ENSDARG00000052826
mus_musculus	Runx3	ENSMUSG00000070691
rattus_norvegicus	Runx3	ENSRNOG00000054217
drosophila_melanogaster	run	FBGN0003300
caenorhabditis_elegans	rnt-1	WBGENE00004393

Paralogs (2): RUNX2 (ENSG00000124813), RUNX1 (ENSG00000159216)

Protein

Protein identifiers

Runt-related transcription factor 3 — Q13761 (reviewed: Q13761)

Alternative names: Acute myeloid leukemia 2 protein, Core-binding factor subunit alpha-3, Oncogene AML-2, Polyomavirus enhancer-binding protein 2 alpha C subunit, SL3-3 enhancer factor 1 alpha C subunit, SL3/AKV core-binding factor alpha C subunit

All UniProt accessions (1): Q13761

UniProt curated annotations — full annotation on UniProt →

Function. Forms the heterodimeric complex core-binding factor (CBF) with CBFB. RUNX members modulate the transcription of their target genes through recognizing the core consensus binding sequence 5’-TGTGGT-3’, or very rarely, 5’-TGCGGT-3’, within their regulatory regions via their runt domain, while CBFB is a non-DNA-binding regulatory subunit that allosterically enhances the sequence-specific DNA-binding capacity of RUNX. The heterodimers bind to the core site of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL3 and GM-CSF promoters. May be involved in the control of cellular proliferation and/or differentiation. In association with ZFHX3, up-regulates CDKN1A promoter activity following TGF-beta stimulation. CBF complexes repress ZBTB7B transcription factor during cytotoxic (CD8+) T cell development. They bind to RUNX-binding sequence within the ZBTB7B locus acting as transcriptional silencer and allowing for cytotoxic T cell differentiation. CBF complexes binding to the transcriptional silencer is essential for recruitment of nuclear protein complexes that catalyze epigenetic modifications to establish epigenetic ZBTB7B silencing. Necessary for the development and survival of sensory neurons expressing parvalbumin.

Subunit / interactions. Heterodimer with CBFB. RUNX3 binds DNA as a monomer and through the Runt domain. DNA-binding is increased by heterodimerization. Interacts with TLE1 and SUV39H1. The tyrosine phosphorylated form (via runt domain) interacts with SRC (via protein kinase domain). Interacts with FYN and LCK. Interacts with FOXP3. Interacts with ZFHX3. Interacts with TBX21.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed in gastric cancer tissues (at protein level).

Post-translational modifications. Phosphorylated on tyrosine residues by SRC. Phosphorylated by LCK and FYN.

Domain organisation. A proline/serine/threonine rich region at the C-terminus is necessary for transcriptional activation of target genes.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13761-1	1	yes
Q13761-2	2

RefSeq proteins (3): NP_001026850, NP_001307601, NP_004341* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000040	AML1_Runt	Family
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR012346	p53/RUNT-type_TF_DNA-bd_sf	Homologous_superfamily
IPR013524	Runt_dom	Domain
IPR013711	RunxI_C_dom	Domain
IPR016554	TF_Runt-rel_RUNX	Family

Pfam: PF00853, PF08504

UniProt features (19 total): sequence conflict 7, compositionally biased region 4, region of interest 3, chain 1, domain 1, cross-link 1, splice variant 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5W69	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13761-F1	61.53	0.29

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 (2): 192, 243

Function

Pathways and Gene Ontology

Reactome pathways

19 pathways

ID	Pathway
R-HSA-4411364	Binding of TCF/LEF:CTNNB1 to target gene promoters
R-HSA-8941855	RUNX3 regulates CDKN1A transcription
R-HSA-8941856	RUNX3 regulates NOTCH signaling
R-HSA-8941858	Regulation of RUNX3 expression and activity
R-HSA-8949275	RUNX3 Regulates Immune Response and Cell Migration
R-HSA-8951430	RUNX3 regulates WNT signaling
R-HSA-8951671	RUNX3 regulates YAP1-mediated transcription
R-HSA-8951911	RUNX3 regulates RUNX1-mediated transcription
R-HSA-8951936	RUNX3 regulates p14-ARF
R-HSA-8952158	RUNX3 regulates BCL2L11 (BIM) transcription
R-HSA-9942503	Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)
R-HSA-162582	Signal Transduction
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-201722	Formation of the beta-catenin:TCF transactivating complex
R-HSA-212436	Generic Transcription Pathway
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878159	Transcriptional regulation by RUNX3

MSigDB gene sets: 451 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_REGULATION_OF_CELL_ACTIVATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, AGGAAGC_MIR5163P, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, WALLACE_PROSTATE_CANCER_RACE_UP, MYOGENIN_Q6, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, PEREZ_TP63_TARGETS, AMIT_EGF_RESPONSE_60_HELA

GO Biological Process (16): negative regulation of transcription by RNA polymerase II (GO:0000122), ossification (GO:0001503), chondrocyte differentiation (GO:0002062), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), protein phosphorylation (GO:0006468), hemopoiesis (GO:0030097), neuron differentiation (GO:0030182), negative regulation of CD4-positive, alpha-beta T cell differentiation (GO:0043371), positive regulation of CD8-positive, alpha-beta T cell differentiation (GO:0043378), regulation of cell differentiation (GO:0045595), negative regulation of cell cycle (GO:0045786), positive regulation of DNA-templated transcription (GO:0045893), peripheral nervous system neuron development (GO:0048935), negative regulation of epithelial cell proliferation (GO:0050680), response to transforming growth factor beta (GO:0071559)

GO Molecular Function (9): 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), transcription corepressor binding (GO:0001222), DNA-binding transcription factor activity (GO:0003700), ATP binding (GO:0005524), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (7): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), core-binding factor complex (GO:0016513)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Transcriptional regulation by RUNX3	9
Formation of the beta-catenin:TCF transactivating complex	1
Differentiation of T cells	1
Signal Transduction	1
Signaling by WNT	1
TCF dependent signaling in response to WNT	1
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
cellular anatomical structure	4
cell differentiation	3
regulation of DNA-templated transcription	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
DNA-templated transcription	2
transcription cis-regulatory region binding	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
nuclear lumen	2
negative regulation of DNA-templated transcription	1
multicellular organismal process	1
cartilage development	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
phosphorylation	1
protein modification process	1
cell development	1
generation of neurons	1
CD4-positive, alpha-beta T cell differentiation	1
regulation of CD4-positive, alpha-beta T cell differentiation	1
negative regulation of alpha-beta T cell differentiation	1
negative regulation of CD4-positive, alpha-beta T cell activation	1
CD8-positive, alpha-beta T cell differentiation	1
regulation of CD8-positive, alpha-beta T cell differentiation	1
positive regulation of alpha-beta T cell differentiation	1
positive regulation of CD8-positive, alpha-beta T cell activation	1
regulation of developmental process	1
regulation of cellular process	1
cell cycle	1
negative regulation of cellular process	1
regulation of cell cycle	1
positive regulation of RNA biosynthetic process	1
neuron development	1
peripheral nervous system neuron differentiation	1
negative regulation of cell population proliferation	1
epithelial cell proliferation	1
regulation of epithelial cell proliferation	1
response to growth factor	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1

Protein interactions and networks

STRING

3128 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RUNX3	CBFB	Q13951	997
RUNX3	CTNNB1	P35222	942
RUNX3	TBX21	Q9UL17	892
RUNX3	RUNX2	Q13950	836
RUNX3	IKZF1	Q13422	832
RUNX3	HNF4A	P41235	829
RUNX3	ZBTB7B	O15156	813
RUNX3	SUV39H1	O43463	808
RUNX3	EP300	Q09472	803
RUNX3	RUNX1	Q01196	803
RUNX3	SMAD3	P84022	780
RUNX3	IKZF3	Q9UKT9	769
RUNX3	NEUROG1	Q92886	728
RUNX3	CACNA1G	O43497	728
RUNX3	TP53	P04637	723

IntAct

67 interactions, top by confidence:

A	B	Type	Score
TCF7L2	CTNNB1	psi-mi:“MI:0914”(association)	0.970
CBFB	RUNX1	psi-mi:“MI:0914”(association)	0.870
RUNX3	CTNNB1	psi-mi:“MI:0914”(association)	0.660
CTNNB1	RUNX3	psi-mi:“MI:0914”(association)	0.660
RUNX3	TCF7L2	psi-mi:“MI:0915”(physical association)	0.660
RUNX3	CTNNB1	psi-mi:“MI:0915”(physical association)	0.660
TCF7L2	RUNX3	psi-mi:“MI:0915”(physical association)	0.660
BRD2	RUNX3	psi-mi:“MI:0915”(physical association)	0.600
RUNX3	BRD2	psi-mi:“MI:0915”(physical association)	0.600
RUNX3	BRD2	psi-mi:“MI:0914”(association)	0.600
BRD2	RUNX3	psi-mi:“MI:0403”(colocalization)	0.600
TLE1	RUNX3	psi-mi:“MI:0915”(physical association)	0.590
RUNX3	TLE1	psi-mi:“MI:0407”(direct interaction)	0.590
RUNX3	TLE1	psi-mi:“MI:0915”(physical association)	0.590
RUNX3	HDAC4	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (98): RUNX3 (Affinity Capture-Western), HDAC5 (Affinity Capture-Western), HDAC1 (Affinity Capture-Western), RUNX3 (Affinity Capture-MS), FANCD2 (Affinity Capture-Western), FANCI (Affinity Capture-Western), Cbfb (Affinity Capture-Western), RUNX3 (Affinity Capture-Western), RUNX3 (Affinity Capture-MS), RUNX3 (Affinity Capture-Western), MYCN (Affinity Capture-Western), RUNX3 (Affinity Capture-Western), MYCN (Reconstituted Complex), RUNX3 (Reconstituted Complex), MALAT1 (Affinity Capture-RNA)

ESM2 similar proteins: A0A084AFG9, A0A0D1C1H8, A0A0D1CY03, A0A142C7A3, A0A364LYQ6, A0A3G1DJJ7, A0A7M4BDQ2, A1CBG9, A1DDX0, A2RA63, B0Y1D1, B0Y8Y9, B4XXY3, B6H7F3, B8N0E6, G0RS98, G3Y415, G4NEE4, G5EB20, N4XMB0, O00167, O13719, P20945, P34440, P87233, P9WER3, Q01196, Q03347, Q04461, Q08775, Q13761, Q13950, Q1K8E7, Q2U9L6, Q4WD42, Q4WV91, Q4WVI6, Q4WW99, Q4WWN2, Q58DB6

Diamond homologs: G5EFQ5, P22814, Q01196, Q03347, Q08775, Q13761, Q13950, Q25520, Q63046, Q64131, Q6PF39, Q9W349, Q9Z2J9, Q9XSB7

SIGNOR signaling

21 interactions.

A	Effect	B	Mechanism
CDK4	down-regulates	RUNX3	phosphorylation
RUNX3	down-regulates	NOTCH1	binding
CyclinD/CDK4	down-regulates	RUNX3	phosphorylation
RUNX3	“up-regulates quantity by expression”	ELANE	“transcriptional regulation”
RUNX3	“down-regulates quantity by repression”	HSPD1	“transcriptional regulation”
RUNX3	“down-regulates quantity by repression”	CFLAR	“transcriptional regulation”
RUNX3	“down-regulates quantity by repression”	TIAL1	“transcriptional regulation”
RUNX3	“down-regulates quantity by repression”	IKBKB	“transcriptional regulation”
RUNX3	“down-regulates quantity by repression”	CHUK	“transcriptional regulation”
RUNX3	“up-regulates quantity by expression”	CAPN10	“transcriptional regulation”
RUNX3	“up-regulates quantity by expression”	DNASE1	“transcriptional regulation”
RUNX3	“down-regulates quantity by repression”	TXN2	“transcriptional regulation”
RUNX3	“up-regulates quantity by expression”	CASP2	“transcriptional regulation”
RUNX3	“up-regulates quantity by expression”	FADD	“transcriptional regulation”
RUNX3	“up-regulates quantity by expression”	ING4	“transcriptional regulation”
RUNX3	“down-regulates quantity by repression”	PEA15	“transcriptional regulation”
RUNX3	“up-regulates quantity by expression”	TRAF6	“transcriptional regulation”
RUNX3	“up-regulates quantity by expression”	ING1	“transcriptional regulation”
SRC	“down-regulates activity”	RUNX3	phosphorylation
MDM2	“down-regulates quantity by destabilization”	RUNX3	ubiquitination
PIM1	“up-regulates quantity”	RUNX3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 29 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
Transcriptional regulation by RUNX3	5	68.0×	5e-07
Formation of the beta-catenin:TCF transactivating complex	5	30.1×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	4
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

770 predictions. Top by Δscore:

Variant	Effect	Δscore
1:24919233:CACTT:C	donor_loss	1.0000
1:24919235:CTT:C	donor_loss	1.0000
1:24919236:TTA:T	donor_loss	1.0000
1:24919237:TACGT:T	donor_loss	1.0000
1:24919238:A:AC	donor_gain	1.0000
1:24919238:ACGT:A	donor_gain	1.0000
1:24919239:C:CC	donor_gain	1.0000
1:24919239:CGT:C	donor_gain	1.0000
1:24919239:CGTC:C	donor_gain	1.0000
1:24927570:TTACC:T	donor_loss	1.0000
1:24927571:TACC:T	donor_loss	1.0000
1:24927572:A:AC	donor_gain	1.0000
1:24927572:AC:A	donor_gain	1.0000
1:24927572:ACC:A	donor_loss	1.0000
1:24927573:C:CC	donor_gain	1.0000
1:24927573:C:G	donor_loss	1.0000
1:24927573:CC:C	donor_gain	1.0000
1:24927573:CCT:C	donor_gain	1.0000
1:24927573:CCTCG:C	donor_gain	1.0000
1:24927727:CCAC:C	acceptor_gain	1.0000
1:24927728:CACC:C	acceptor_gain	1.0000
1:24927731:CTGA:C	acceptor_loss	1.0000
1:24929584:CACCT:C	donor_loss	1.0000
1:24929585:A:AC	donor_gain	1.0000
1:24929585:AC:A	donor_gain	1.0000
1:24929586:C:CA	donor_gain	1.0000
1:24929586:CC:C	donor_gain	1.0000
1:24929586:CCT:C	donor_gain	1.0000
1:24907253:CCGTA:C	donor_loss	0.9900
1:24907254:CGTA:C	donor_loss	0.9900

AlphaMissense

2713 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:24902136:A:G	W412R	1.000
1:24902136:A:T	W412R	1.000
1:24919241:T:A	R181S	1.000
1:24919241:T:G	R181S	1.000
1:24919242:C:A	R181I	1.000
1:24919242:C:G	R181T	1.000
1:24919251:C:T	R178Q	1.000
1:24919252:G:A	R178W	1.000
1:24919254:G:T	P177H	1.000
1:24919255:G:A	P177S	1.000
1:24919257:C:A	G176V	1.000
1:24919257:C:G	G176A	1.000
1:24919257:C:T	G176E	1.000
1:24919258:C:G	G176R	1.000
1:24919258:C:T	G176R	1.000
1:24919259:G:C	D175E	1.000
1:24919259:G:T	D175E	1.000
1:24919260:T:A	D175V	1.000
1:24919260:T:C	D175G	1.000
1:24919260:T:G	D175A	1.000
1:24919261:C:A	D175Y	1.000
1:24919261:C:G	D175H	1.000
1:24919261:C:T	D175N	1.000
1:24919263:A:G	V174A	1.000
1:24919263:A:T	V174E	1.000
1:24919264:C:A	V174L	1.000
1:24919264:C:G	V174L	1.000
1:24919264:C:T	V174M	1.000
1:24919266:G:A	T173I	1.000
1:24919266:G:C	T173S	1.000

dbSNP variants (sampled 300 via entrez): RS1000081063 (1:24956278 T>C), RS1000100250 (1:24918414 C>G), RS1000174179 (1:24902864 T>C,G), RS1000295993 (1:24945474 C>A,T), RS1000302882 (1:24940645 G>T), RS1000334148 (1:24939420 A>G), RS1000381190 (1:24908116 G>A,T), RS1000402915 (1:24939630 C>G,T), RS1000404856 (1:24903089 G>A), RS1000452444 (1:24946654 T>C), RS1000458157 (1:24913302 G>A), RS1000469037 (1:24945679 C>T), RS1000555552 (1:24901960 C>T), RS1000558396 (1:24899122 G>A,T), RS1000668057 (1:24940457 G>A)

Disease associations

OMIM: gene MIM:600210 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

39 associations (top):

Study	Trait	p-value
GCST000612_13	Celiac disease	2.000000e-10
GCST001149_13	Ankylosing spondylitis	9.000000e-11
GCST001785_1	Crohn’s disease	9.000000e-06
GCST002349_3	Response to protease inhibitor treatment in hepatitis c (peak serum total bilirubin levels)	2.000000e-06
GCST002935_14	Lead levels	5.000000e-06
GCST003268_33	Psoriasis vulgaris	2.000000e-08
GCST003983_26	Male-pattern baldness	5.000000e-11
GCST004861_25	Itch intensity from mosquito bite	9.000000e-09
GCST004862_163	Itch intensity from mosquito bite adjusted by bite size	2.000000e-06
GCST004863_40	Mosquito bite size	3.000000e-07
GCST005038_29	Allergic disease (asthma, hay fever or eczema)	6.000000e-13
GCST005116_2	Male-pattern baldness	5.000000e-17
GCST005116_3	Male-pattern baldness	2.000000e-19
GCST005116_32	Male-pattern baldness	1.000000e-20
GCST005523_2	Celiac disease	4.000000e-06
GCST005527_23	Psoriasis	2.000000e-12
GCST005528_31	Juvenile idiopathic arthritis (oligoarticular or rheumatoid factor-negative polyarticular)	5.000000e-07
GCST005529_15	Ankylosing spondylitis	1.000000e-14
GCST005529_33	Ankylosing spondylitis	3.000000e-15
GCST005987_20	Albumin-globulin ratio	1.000000e-12
GCST005990_36	Non-albumin protein levels	2.000000e-12
GCST006661_182	Male-pattern baldness	1.000000e-10
GCST006661_258	Male-pattern baldness	5.000000e-21
GCST006661_48	Male-pattern baldness	2.000000e-11
GCST007563_16	Allergic disease (asthma, hay fever or eczema)	1.000000e-08
GCST007564_8	Asthma or allergic disease (pleiotropy)	1.000000e-08
GCST008568_11	IgA levels	8.000000e-55
GCST008916_73	Asthma	4.000000e-08
GCST009028_60	Adverse response to drug	8.000000e-07
GCST009597_258	Multiple sclerosis	1.000000e-09

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004570	bilirubin measurement
EFO:0005657	response to protease inhibitor
EFO:1001494	psoriasis vulgaris
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0005128	albumin:globulin ratio measurement
EFO:0009658	adverse effect
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004587	lymphocyte count
EFO:0007986	reticulocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	7
Decitabine	decreases reaction, increases expression, affects expression, affects methylation, decreases expression	6
Cisplatin	affects expression, decreases expression, increases response to substance	4
Tobacco Smoke Pollution	decreases expression, decreases methylation, increases expression	4
(+)-JQ1 compound	decreases expression	3
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Nickel	increases expression	2
Aflatoxin B1	decreases expression, increases methylation, decreases reaction	2
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
terbufos	increases methylation	1
arsenite	decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	decreases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
Sorafenib	affects reaction, affects response to substance	1
Arsenic Trioxide	increases expression	1
Fulvestrant	decreases methylation, affects cotreatment	1
Amphotericin B	decreases expression	1
Arsenic	affects methylation	1
Azacitidine	affects methylation	1
Cyclophosphamide	decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases activity	1

Cellosaurus cell lines

9 cell lines: 6 cancer cell line, 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A5Y8	SEES3-1V human RUNX3, clone1	Embryonic stem cell	Male
CVCL_A5Y9	SEES3-1V human RUNX3, clone2	Embryonic stem cell	Male
CVCL_A5Z0	SEES3-1V human RUNX3, clone3	Embryonic stem cell	Male
CVCL_B8P3	Abcam HCT 116 RUNX3 KO	Cancer cell line	Male
CVCL_B9RF	Abcam A-549 RUNX3 KO	Cancer cell line	Male
CVCL_D2H7	Abcam MCF-7 RUNX3 KO	Cancer cell line	Female
CVCL_TJ86	HAP1 RUNX3 (-) 1	Cancer cell line	Male
CVCL_XS35	HAP1 RUNX3 (-) 2	Cancer cell line	Male
CVCL_XS36	HAP1 RUNX3 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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