HES3

Summary

HES3 (hes family bHLH transcription factor 3, HGNC:26226) is a protein-coding gene on chromosome 1p36.31, encoding Transcription factor HES-3 (Q5TGS1). Transcriptional repressor of genes that require a bHLH protein for their transcription.

Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of neurogenesis. Predicted to act upstream of or within several processes, including nervous system development; regulation of timing of neuron differentiation; and regulation of transcription by RNA polymerase II. Predicted to be located in chromatin. Predicted to be active in nucleus.

Source: NCBI Gene 390992 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 30 total
• MANE Select transcript: NM_001024598

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26226
Approved symbol	HES3
Name	hes family bHLH transcription factor 3
Location	1p36.31
Locus type	gene with protein product
Status	Approved
Aliases	bHLHb43
Ensembl gene	ENSG00000173673
Ensembl biotype	protein_coding
OMIM	609971
Entrez	390992

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000377898, ENST00000706530

RefSeq mRNA: 1 — MANE Select: NM_001024598 NM_001024598

CCDS: CCDS41238

Canonical transcript exons

ENST00000377898 — 4 exons

Exon	Start	End
ENSE00001182530	6244548	6244629
ENSE00001475445	6245110	6245578
ENSE00003996079	6244351	6244446
ENSE00003996080	6244179	6244241

Expression profiles

Bgee: expression breadth tissue_specific, 1 present calls, max score 37.20.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.2279 / max 429.4280, expressed in 142 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
367	3.2279	142

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
bone marrow	UBERON:0002371	31.74	gold quality
muscle tissue	UBERON:0002385	31.06	gold quality
sural nerve	UBERON:0015488	30.93	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
prefrontal cortex	UBERON:0000451	29.22	gold quality
duodenum	UBERON:0002114	28.14	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	27.79	silver quality
lymph node	UBERON:0000029	27.57	gold quality
leukocyte	CL:0000738	27.06	gold quality
tonsil	UBERON:0002372	27.05	gold quality
monocyte	CL:0000576	27.01	gold quality
urinary bladder	UBERON:0001255	26.89	gold quality
islet of Langerhans	UBERON:0000006	26.55	gold quality
vermiform appendix	UBERON:0001154	26.42	gold quality
blood	UBERON:0000178	26.14	gold quality
gall bladder	UBERON:0002110	25.98	gold quality
placenta	UBERON:0001987	25.81	gold quality
frontal cortex	UBERON:0001870	25.21	gold quality
Brodmann (1909) area 9	UBERON:0013540	25.01	gold quality
primary visual cortex	UBERON:0002436	24.61	gold quality
superior frontal gyrus	UBERON:0002661	24.08	gold quality
pancreas	UBERON:0001264	24.05	gold quality
right hemisphere of cerebellum	UBERON:0014890	23.92	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.33

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
HES1	Repression

Upstream regulators (CollecTRI, top): HEY1, NANOG, POU5F1, RBPJ, SOX2

Literature-anchored findings (GeneRIF, showing 7)

• CXorf6 transactivates the Hes3 promoter, augments testosterone production (PMID:18162467)
• Hes3 is expressed in cultures from glioblastoma multiforme which express neural stem cell markers (PMID:23393614)
• expression of the transcription factor Hes3 in the mouse and human ocular surface, and in pterygium (PMID:24512568)
• Data show that transcription factor Hes3 is expressed in adult pancreatic islets and dissociated cultures of pancreatic islet cells. (PMID:25371201)
• The STAT3-Ser/Hes3 Signaling Axis was first identified as a major regulator of neural stem cells and, subsequently, cancer stem cells (PMID:26783739)
• HES3 overexpression is associated with impaired myogenic differentiation and rhabdomyosarcoma tumorigenesis. (PMID:29869612)
• Hes3 regulated cell proliferation and lung cancer invasion.Hes3 regulated Cyclin D1, Cyclin D3 and MMP7 expression in lung cancer cells. (PMID:30911281)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	her3	ENSDARG00000076857
mus_musculus	Hes3	ENSMUSG00000028946
rattus_norvegicus	Hes3	ENSRNOG00000010893
drosophila_melanogaster	E(spl)m8-HLH	FBGN0000591
drosophila_melanogaster	E(spl)m3-HLH	FBGN0002609
drosophila_melanogaster	E(spl)m5-HLH	FBGN0002631
drosophila_melanogaster	E(spl)m7-HLH	FBGN0002633
drosophila_melanogaster	E(spl)mbeta-HLH	FBGN0002733
drosophila_melanogaster	E(spl)mdelta-HLH	FBGN0002734
drosophila_melanogaster	E(spl)mgamma-HLH	FBGN0002735
drosophila_melanogaster	Hesr	FBGN0030899
drosophila_melanogaster	cwo	FBGN0259938

Paralogs (12): HES2 (ENSG00000069812), HES1 (ENSG00000114315), BHLHE41 (ENSG00000123095), BHLHE40 (ENSG00000134107), HEY2 (ENSG00000135547), HES6 (ENSG00000144485), HEYL (ENSG00000163909), HEY1 (ENSG00000164683), HES7 (ENSG00000179111), HELT (ENSG00000187821), HES4 (ENSG00000188290), HES5 (ENSG00000197921)

Protein

Protein identifiers

Transcription factor HES-3 — Q5TGS1 (reviewed: Q5TGS1)

Alternative names: Class B basic helix-loop-helix protein 43, Hairy and enhancer of split 3

All UniProt accessions (2): Q5TGS1, A0A9L9PX90

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor of genes that require a bHLH protein for their transcription.

Subunit / interactions. Transcription repression requires formation of a complex with a corepressor protein of the Groucho/TLE family.

Subcellular location. Nucleus.

Domain organisation. Has a particular type of basic domain (presence of a helix-interrupting proline) that binds to the N-box (CACNAG), rather than the canonical E-box (CANNTG). The C-terminal WRPW motif is a transcriptional repression domain necessary for the interaction with Groucho/TLE family members, transcriptional corepressors recruited to specific target DNA by Hairy-related proteins.

RefSeq proteins (1): NP_001019769* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR050370	HES_HEY	Family

Pfam: PF00010

UniProt features (6 total): domain 2, chain 1, region of interest 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5TGS1-F1	64.65	0.16

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 53 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_ANTERIOR_POSTERIOR_PATTERN_SPECIFICATION, SHIN_B_CELL_LYMPHOMA_CLUSTER_2, LEE_AGING_NEOCORTEX_DN, GOBP_REGULATION_OF_CELL_DEVELOPMENT, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, YOSHIMURA_MAPK8_TARGETS_UP, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, chr1p36, MEISSNER_BRAIN_HCP_WITH_H3K27ME3, MEISSNER_NPC_HCP_WITH_H3K4ME2, MIKKELSEN_MEF_HCP_WITH_H3K27ME3, SHEPARD_CRASH_AND_BURN_MUTANT_DN

GO Biological Process (3): regulation of transcription by RNA polymerase II (GO:0006357), anterior/posterior pattern specification (GO:0009952), regulation of neurogenesis (GO:0050767)

GO Molecular Function (4): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), protein dimerization activity (GO:0046983), DNA binding (GO:0003677)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
regionalization	1
neurogenesis	1
regulation of nervous system development	1
regulation of cell development	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
protein binding	1
nucleic acid binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

602 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HES3	HEYL	Q9NQ87	600
HES3	HES6	Q96HZ4	569
HES3	HEY1	Q9Y5J3	557
HES3	MIXL1	Q9H2W2	516
HES3	MAMLD1	Q13495	504
HES3	RBPJ	Q06330	469
HES3	NHLH1	Q02575	462
HES3	NKX2-5	P52952	451
HES3	FGF2	P09038	431
HES3	TLE4	Q04727	429
HES3	POU5F1	P31359	425
HES3	ASCL1	P50553	417
HES3	JAG1	P78504	411
HES3	PAX6	P26367	409
HES3	LHX9	Q9NQ69	406

IntAct

2 interactions, top by confidence:

A	B	Type	Score
HES3	SRC	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): SRC (Affinity Capture-MS), HCCS (Affinity Capture-MS), NRN1 (Affinity Capture-MS), HES3 (Affinity Capture-MS)

ESM2 similar proteins: A0A5F9ZHS7, A1YGK1, A2T7E6, A8MZG2, O08574, O43593, O60393, O75593, O88621, O95231, P0C1T1, P0CG20, P20428, P97609, Q04667, Q17QR5, Q2KIS6, Q2M1V0, Q2T9Q7, Q32LE6, Q497V6, Q5JUK2, Q5M844, Q5RJB0, Q5TGS1, Q61645, Q61657, Q6ZMY3, Q6ZN32, Q6ZNG2, Q7RTU1, Q8BZW2, Q8CGW9, Q8IWN7, Q8IXT2, Q8IZ20, Q8N1L9, Q8N7G0, Q8N944, Q8N9Y4

Diamond homologs: G5EF76, O54792, O57337, P13097, P14003, P29303, P35428, P35429, P70120, Q00P32, Q01068, Q01069, Q01070, Q01071, Q03062, Q04666, Q04667, Q07291, Q14469, Q26263, Q28HA8, Q3ZBG4, Q5PPM5, Q5TA89, Q5TGS1, Q61657, Q6IRB2, Q6PBD4, Q8AVU4, Q8BKT2, Q8UW72, Q8UW74, Q90VV1, Q90Z12, Q9BYE0, Q9HCC6, Q9Y543, A6NFD8, P13096, P13098

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

363 predictions. Top by Δscore:

Variant	Effect	Δscore
1:6244443:CCAGG:C	donor_loss	1.0000
1:6244444:CAGG:C	donor_loss	1.0000
1:6244445:AGGT:A	donor_loss	1.0000
1:6244446:GGTGA:G	donor_loss	1.0000
1:6244447:G:GA	donor_loss	1.0000
1:6244546:A:AG	acceptor_gain	1.0000
1:6244547:G:GG	acceptor_gain	1.0000
1:6244257:GGAC:G	donor_gain	0.9900
1:6244447:G:GG	donor_gain	0.9900
1:6244448:T:A	donor_loss	0.9900
1:6244537:T:TA	acceptor_gain	0.9900
1:6244541:C:A	acceptor_gain	0.9900
1:6244542:G:A	acceptor_gain	0.9900
1:6244543:GGTA:G	acceptor_loss	0.9900
1:6244544:GTAGA:G	acceptor_loss	0.9900
1:6244627:AAG:A	donor_loss	0.9900
1:6244630:G:A	donor_loss	0.9900
1:6244594:TG:T	donor_gain	0.9800
1:6244595:G:GT	donor_gain	0.9800
1:6245106:ACAG:A	acceptor_gain	0.9800
1:6245106:ACAGG:A	acceptor_gain	0.9800
1:6245108:A:AG	acceptor_gain	0.9800
1:6245108:AG:A	acceptor_gain	0.9800
1:6245108:AGG:A	acceptor_gain	0.9800
1:6245109:G:GG	acceptor_gain	0.9800
1:6245109:GG:G	acceptor_gain	0.9800
1:6245109:GGG:G	acceptor_gain	0.9800
1:6245109:GGGC:G	acceptor_gain	0.9800
1:6245109:GGGCT:G	acceptor_gain	0.9800
1:6244258:G:T	donor_gain	0.9700

AlphaMissense

1178 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:6244590:A:C	S42R	0.997
1:6244592:C:A	S42R	0.997
1:6244592:C:G	S42R	0.997
1:6244391:T:C	I9T	0.996
1:6244571:G:C	K35N	0.995
1:6244571:G:T	K35N	0.995
1:6244567:A:T	E34V	0.993
1:6244378:C:A	R5S	0.992
1:6244569:A:C	K35Q	0.992
1:6244582:T:A	L39Q	0.990
1:6244370:A:T	E2V	0.989
1:6244371:G:C	E2D	0.989
1:6244371:G:T	E2D	0.989
1:6244412:T:C	L16P	0.989
1:6244416:G:C	K17N	0.989
1:6244416:G:T	K17N	0.989
1:6244369:G:A	E2K	0.985
1:6244568:G:C	E34D	0.985
1:6244568:G:T	E34D	0.985
1:6244569:A:G	K35E	0.985
1:6244388:G:C	R8P	0.984
1:6244579:T:C	I38T	0.984
1:6244582:T:C	L39P	0.984
1:6244395:T:A	N10K	0.983
1:6244395:T:G	N10K	0.983
1:6244374:A:C	K3N	0.982
1:6244374:A:T	K3N	0.982
1:6244391:T:G	I9S	0.982
1:6244412:T:A	L16H	0.982
1:6244566:G:A	E34K	0.982

dbSNP variants (sampled 300 via entrez): RS1000041902 (1:6244851 G>C), RS1001336111 (1:6242577 C>T), RS1001826607 (1:6245892 C>A,T), RS1002664761 (1:6243055 T>G), RS1002686824 (1:6242861 A>G), RS1003020465 (1:6242768 C>A), RS1003357342 (1:6245566 T>A), RS1003868552 (1:6243834 G>C,T), RS1004516957 (1:6242715 G>A), RS1004630083 (1:6242429 C>T), RS1006189645 (1:6243956 G>A), RS1006241969 (1:6244871 G>A), RS1006474065 (1:6244929 C>G,T), RS1007510131 (1:6242198 G>C), RS1008743937 (1:6242322 G>A)

Disease associations

OMIM: gene MIM:609971 | 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

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
decabromobiphenyl ether	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
tetrabromobisphenol A	decreases expression	1
tetrachlorodian	decreases expression	1
Cyclic AMP	affects cotreatment, decreases expression	1
Ascorbic Acid	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	increases expression	1
1-Methyl-4-phenylpyridinium	decreases expression	1

Clinical trials (associated diseases)

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