HES4

Summary

HES4 (hes family bHLH transcription factor 4, HGNC:24149) is a protein-coding gene on chromosome 1p36.33, encoding Transcription factor HES-4 (Q9HCC6). Transcriptional repressor.

Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in cell differentiation; nervous system development; and regulation of transcription by RNA polymerase II. Predicted to be located in chromatin. Predicted to be active in nucleus.

Source: NCBI Gene 57801 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 66 total
• MANE Select transcript: NM_021170

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24149
Approved symbol	HES4
Name	hes family bHLH transcription factor 4
Location	1p36.33
Locus type	gene with protein product
Status	Approved
Aliases	bHLHb42
Ensembl gene	ENSG00000188290
Ensembl biotype	protein_coding
OMIM	608060
Entrez	57801

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000304952, ENST00000428771, ENST00000481869, ENST00000484667, ENST00000854802

RefSeq mRNA: 3 — MANE Select: NM_021170 NM_001142467, NM_001410700, NM_021170

CCDS: CCDS44034, CCDS5, CCDS90837

Canonical transcript exons

ENST00000304952 — 4 exons

Exon	Start	End
ENSE00001374237	999692	999787
ENSE00001424451	999866	1000097
ENSE00001801835	999526	999613
ENSE00001934557	998964	999432

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 95.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.1586 / max 799.4234, expressed in 1404 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9682	8.8956	1264
9681	3.4505	901
9683	1.5715	732
9684	0.5171	301
9678	0.3257	152
9679	0.2506	71
9680	0.1475	58

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	95.61	gold quality
popliteal artery	UBERON:0002250	94.89	gold quality
tibial artery	UBERON:0007610	94.89	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.66	gold quality
apex of heart	UBERON:0002098	92.83	gold quality
aorta	UBERON:0000947	92.35	gold quality
coronary artery	UBERON:0001621	92.31	gold quality
left coronary artery	UBERON:0001626	92.24	gold quality
right coronary artery	UBERON:0001625	92.12	gold quality
putamen	UBERON:0001874	92.07	gold quality
ganglionic eminence	UBERON:0004023	91.79	gold quality
right uterine tube	UBERON:0001302	91.67	gold quality
right atrium auricular region	UBERON:0006631	91.55	gold quality
cardiac atrium	UBERON:0002081	91.25	gold quality
nucleus accumbens	UBERON:0001882	90.55	gold quality
caudate nucleus	UBERON:0001873	89.94	gold quality
amniotic fluid	UBERON:0000173	89.77	gold quality
heart left ventricle	UBERON:0002084	89.64	gold quality
left uterine tube	UBERON:0001303	89.37	gold quality
cardiac ventricle	UBERON:0002082	89.36	gold quality
ascending aorta	UBERON:0001496	89.32	gold quality
cortical plate	UBERON:0005343	89.12	gold quality
thoracic aorta	UBERON:0001515	89.08	gold quality
heart	UBERON:0000948	88.71	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	88.61	gold quality
hypothalamus	UBERON:0001898	88.56	gold quality
ectocervix	UBERON:0012249	88.45	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.36	gold quality
lower esophagus	UBERON:0013473	88.30	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.25	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-MTAB-10485	yes	1001.54
E-MTAB-7008	yes	93.26
E-CURD-114	yes	55.15
E-MTAB-10287	yes	49.36
E-MTAB-6701	yes	47.51
E-HCAD-11	yes	23.87
E-GEOD-125970	yes	23.66
E-HCAD-5	yes	21.33
E-ANND-3	yes	11.52
E-GEOD-134144	yes	9.79
E-CURD-46	yes	9.60
E-HCAD-56	no	1268.16
E-MTAB-8894	no	963.81
E-GEOD-114530	no	900.80
E-MTAB-9689	no	171.55

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
ASCL1	Activation
CDKN1A	Repression

Literature-anchored findings (GeneRIF, showing 4)

• Epigenetic dysregulation of HES4 could play a critical role in modifying Huntington’s disease pathogenesis and severity. (PMID:25480889)
• Overexpression and knockdown studies demonstrated that Hes4 promotes osteogenesis resulting in an increase in Runx2, osteocalcin, osteopontin, and bone sialoprotein expression in BMSC. (PMID:25579220)
• Hes4 overexpression promotes a more aggressive tumor phenotype by preventing osteoblastic differentiation of osteosarcoma cells. Hes4 expression may allow for the stratification of patients into good or poor responders to chemotherapy at diagnosis. (PMID:27786411)
• HES1 and HES4 have non-redundant roles downstream of Notch during early human T-cell development. (PMID:31919081)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	her9	ENSDARG00000056438
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

Paralogs (12): HES2 (ENSG00000069812), HES1 (ENSG00000114315), BHLHE41 (ENSG00000123095), BHLHE40 (ENSG00000134107), HEY2 (ENSG00000135547), HES6 (ENSG00000144485), HEYL (ENSG00000163909), HEY1 (ENSG00000164683), HES3 (ENSG00000173673), HES7 (ENSG00000179111), HELT (ENSG00000187821), HES5 (ENSG00000197921)

Protein

Protein identifiers

Transcription factor HES-4 — Q9HCC6 (reviewed: Q9HCC6)

Alternative names: Class B basic helix-loop-helix protein 42, Hairy and enhancer of split 4, bHLH factor Hes4

All UniProt accessions (3): D6REB3, E9PB28, Q9HCC6

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor. Binds DNA on N-box motifs: 5’-CACNAG-3'.

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 (3): NP_001135939, NP_001397629, NP_066993* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003650	Orange_dom	Domain
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR050370	HES_HEY	Family

Pfam: PF00010, PF07527

UniProt features (8 total): domain 2, region of interest 2, compositionally biased region 2, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HCC6-F1	73.25	0.33

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 112 (showing top): GOZGIT_ESR1_TARGETS_DN, GOBP_ANTERIOR_POSTERIOR_PATTERN_SPECIFICATION, LIAO_METASTASIS, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, ZHOU_INFLAMMATORY_RESPONSE_LIVE_UP, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, chr1p36, HORIUCHI_WTAP_TARGETS_UP, LU_EZH2_TARGETS_UP, GOBP_NEGATIVE_REGULATION_OF_TRANSCRIPTION_BY_RNA_POLYMERASE_II, GOBP_NEGATIVE_REGULATION_OF_NUCLEOBASE_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOMF_TRANSCRIPTION_REGULATOR_ACTIVITY, CSHL1_TARGET_GENES, FOXD3_TARGET_GENES, FOXE1_TARGET_GENES

GO Biological Process (5): regulation of transcription by RNA polymerase II (GO:0006357), nervous system development (GO:0007399), anterior/posterior pattern specification (GO:0009952), cell differentiation (GO:0030154), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (5): 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), protein binding (GO:0005515)

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
system development	1
regionalization	1
cellular developmental process	1
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
regulation of transcription by RNA polymerase II	1
protein binding	1
nucleic acid binding	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

676 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HES4	NRARP	Q7Z6K4	571
HES4	NOTCH3	Q9UM47	550
HES4	NOTCH1	P46531	544
HES4	JAG2	Q9Y219	540
HES4	MAML1	Q92585	514
HES4	DTX1	Q86Y01	500
HES4	JAG1	P78504	499
HES4	DLL1	O00548	497
HES4	NOTCH2	Q04721	483
HES4	NOTCH4	Q99466	458
HES4	DLL4	Q9NR61	457
HES4	RBPJ	Q06330	447
HES4	DLL3	Q9NYJ7	433
HES4	MAML2	Q8IZL2	412
HES4	HES3	Q5TGS1	370

IntAct

51 interactions, top by confidence:

A	B	Type	Score
DR1	HES4	psi-mi:“MI:0915”(physical association)	0.560
	HES4	psi-mi:“MI:0915”(physical association)	0.560
GTF2B	HES4	psi-mi:“MI:0915”(physical association)	0.560
HES4		psi-mi:“MI:0915”(physical association)	0.560
GTF3C3	HES4	psi-mi:“MI:0915”(physical association)	0.560
SNCA	HES4	psi-mi:“MI:0915”(physical association)	0.560
HTT	HES4	psi-mi:“MI:0915”(physical association)	0.560
TARDBP	HES4	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (24): HES4 (Affinity Capture-RNA), HES4 (Affinity Capture-MS), HES4 (Affinity Capture-RNA), GSDMA (Affinity Capture-MS), FCGRT (Affinity Capture-MS), HAL (Affinity Capture-MS), TGM1 (Affinity Capture-MS), PUS1 (Affinity Capture-MS), SDR9C7 (Affinity Capture-MS), SERPINB3 (Affinity Capture-MS), PAFAH2 (Affinity Capture-MS), ALOX12B (Affinity Capture-MS), SERPINB8 (Affinity Capture-MS), CTSV (Affinity Capture-MS), CTSH (Affinity Capture-MS)

ESM2 similar proteins: A7YY73, D3YY23, O08580, O09017, O54791, O54792, O57337, O95382, P10588, P11474, P13097, P35428, P35429, P43136, P70120, Q00P32, Q01069, Q01070, Q01071, Q03062, Q04666, Q07291, Q0VBL6, Q14469, Q1L5Z9, Q28HA8, Q3U0S6, Q3ZBG4, Q5QJV7, Q5TA89, Q5U651, Q6P9Q4, Q8AXV5, Q8AXV6, Q8BKT2, Q8BLS7, Q8K1S6, Q8N100, Q8R5G7, Q8WWL2

Diamond homologs: A0MLS5, A6NFD8, O00327, O14503, O35779, O54792, O57337, O61734, O88529, P13097, P14003, P29303, P35428, P35429, P70120, Q00P32, Q01069, Q03062, Q04666, Q14469, Q26263, Q28HA8, Q2KIN4, Q2NL18, Q3ZBG4, Q5PPM5, Q5R4T2, Q5RAI7, Q5TA89, Q66KK8, Q6IRB2, Q6PBD4, Q6QB00, Q6YGZ5, Q7KM13, Q7TS99, Q8AVU4, Q8AXV5, Q8AXV6, Q8BKT2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	65
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

221 predictions. Top by Δscore:

Variant	Effect	Δscore
1:999428:CGCGG:C	acceptor_gain	1.0000
1:999430:CGG:C	acceptor_gain	1.0000
1:999433:C:CC	acceptor_gain	1.0000
1:999609:GAGCT:G	acceptor_gain	1.0000
1:999611:GCTC:G	acceptor_loss	1.0000
1:999612:CT:C	acceptor_gain	1.0000
1:999613:TCTG:T	acceptor_loss	1.0000
1:999614:C:CC	acceptor_gain	1.0000
1:999615:T:A	acceptor_loss	1.0000
1:999691:CCT:C	donor_gain	1.0000
1:999429:GCGG:G	acceptor_gain	0.9900
1:999430:CGGC:C	acceptor_gain	0.9900
1:999431:GG:G	acceptor_gain	0.9900
1:999433:CTGC:C	acceptor_loss	0.9900
1:999434:T:C	acceptor_loss	0.9900
1:999442:C:CT	acceptor_gain	0.9900
1:999443:G:T	acceptor_gain	0.9900
1:999520:CCTCA:C	donor_loss	0.9900
1:999521:CTCA:C	donor_loss	0.9900
1:999522:TCA:T	donor_loss	0.9900
1:999523:CAC:C	donor_loss	0.9900
1:999524:A:C	donor_loss	0.9900
1:999524:AC:A	donor_gain	0.9900
1:999525:CC:C	donor_gain	0.9900
1:999610:AGCT:A	acceptor_gain	0.9900
1:999621:C:CT	acceptor_gain	0.9900
1:999687:CTTA:C	donor_loss	0.9900
1:999688:TTA:T	donor_loss	0.9900
1:999689:TA:T	donor_loss	0.9900
1:999691:C:A	donor_loss	0.9900

AlphaMissense

1377 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:999747:A:G	I50T	0.999
1:999760:G:T	R46S	0.998
1:999767:C:A	E43D	0.998
1:999767:C:G	E43D	0.998
1:999769:C:T	E43K	0.998
1:999779:C:A	K39N	0.998
1:999779:C:G	K39N	0.998
1:999576:A:T	L81Q	0.997
1:999591:T:A	E76V	0.997
1:999726:A:T	L57H	0.996
1:999735:A:T	L54H	0.996
1:999768:T:A	E43V	0.996
1:999781:T:C	K39E	0.996
1:999726:A:G	L57P	0.995
1:999754:C:G	A48P	0.995
1:999383:G:C	F114L	0.994
1:999383:G:T	F114L	0.994
1:999385:A:G	F114L	0.994
1:999723:T:A	K58I	0.994
1:999743:G:C	N51K	0.994
1:999743:G:T	N51K	0.994
1:999747:A:T	I50N	0.994
1:999764:C:A	K44N	0.994
1:999764:C:G	K44N	0.994
1:999374:A:C	C117W	0.993
1:999747:A:C	I50S	0.993
1:999579:A:G	I80T	0.992
1:999579:A:T	I80N	0.992
1:999589:T:G	K77Q	0.992
1:999592:C:T	E76K	0.992

dbSNP variants (sampled 300 via entrez): RS1000288620 (1:998942 A>G), RS1000627427 (1:999719 G>A,T), RS1001256418 (1:1000738 C>A,G), RS1003313473 (1:1001951 T>C), RS1004127549 (1:1001239 G>A), RS1004219406 (1:1001054 G>A), RS1004692703 (1:998562 G>A), RS1005040875 (1:999023 G>A,T), RS1005330010 (1:1000459 T>A), RS1007045161 (1:1001473 G>A), RS1007663951 (1:1000287 C>A,T), RS1007789682 (1:1000454 G>A), RS1008050500 (1:1001723 C>A,T), RS1008602796 (1:1001974 G>A), RS1008674972 (1:998877 G>A)

Disease associations

OMIM: gene MIM:608060 | disease phenotypes: MIM:616126

GenCC curated gene-disease

Mondo (1): Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency (MONDO:0014502)

Orphanet (1): Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency (Orphanet:319563)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010242_364	HDL cholesterol levels	1.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	increases expression	2
Benzo(a)pyrene	decreases expression, increases expression	2
Cisplatin	affects expression, affects cotreatment, decreases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Valproic Acid	affects expression, increases methylation	2
Cyclosporine	increases expression	2
Aflatoxin B1	affects expression, increases expression	2
Cadmium Chloride	increases expression	2
Particulate Matter	affects cotreatment, increases abundance, increases expression, decreases expression	2
triphenyl phosphate	affects expression	1
lead acetate	decreases expression	1
sodium arsenate	increases abundance, increases expression	1
trichostatin A	increases expression	1
beta-lapachone	increases expression	1
zinc chromate	decreases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
2-palmitoylglycerol	increases expression	1
K 7174	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
MRK 003	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	increases expression	1
Decitabine	affects expression	1
Zoledronic Acid	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2N3	Abcam A-549 HES4 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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