HES2

Summary

HES2 (hes family bHLH transcription factor 2, HGNC:16005) is a protein-coding gene on chromosome 1p36.31, encoding Transcription factor HES-2 (Q9Y543). Transcriptional repressor of genes that require a bHLH protein for their transcription.

Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of neurogenesis. Predicted to be located in chromatin. Predicted to be active in nucleus.

Source: NCBI Gene 54626 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 28 total
• MANE Select transcript: NM_019089

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16005
Approved symbol	HES2
Name	hes family bHLH transcription factor 2
Location	1p36.31
Locus type	gene with protein product
Status	Approved
Aliases	bHLHb40
Ensembl gene	ENSG00000069812
Ensembl biotype	protein_coding
OMIM	609970
Entrez	54626

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 8 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000377834, ENST00000377836, ENST00000377837, ENST00000471190, ENST00000487437, ENST00000489730, ENST00000854984, ENST00000854985, ENST00000956305

RefSeq mRNA: 1 — MANE Select: NM_019089 NM_019089

CCDS: CCDS30574

Canonical transcript exons

ENST00000377834 — 4 exons

Exon	Start	End
ENSE00000734533	6419241	6419340
ENSE00001475263	6415232	6419153
ENSE00001475267	6419776	6419919
ENSE00002817476	6419607	6419702

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 87.79.

FANTOM5 (CAGE): breadth broad, TPM avg 3.6237 / max 146.4025, expressed in 548 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10034	3.6237	548

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus mucosa	UBERON:0002469	87.79	gold quality
lower esophagus mucosa	UBERON:0035834	86.14	gold quality
mucosa of transverse colon	UBERON:0004991	85.22	gold quality
buccal mucosa cell	CL:0002336	83.52	silver quality
esophagus squamous epithelium	UBERON:0006920	83.07	gold quality
placenta	UBERON:0001987	82.34	gold quality
skin of abdomen	UBERON:0001416	81.98	gold quality
gingival epithelium	UBERON:0001949	81.88	gold quality
gingiva	UBERON:0001828	81.15	gold quality
skin of leg	UBERON:0001511	80.38	gold quality
squamous epithelium	UBERON:0006914	79.49	gold quality
zone of skin	UBERON:0000014	79.03	gold quality
epithelium of esophagus	UBERON:0001976	77.77	gold quality
vagina	UBERON:0000996	76.74	gold quality
endometrium epithelium	UBERON:0004811	76.66	gold quality
right uterine tube	UBERON:0001302	75.33	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	74.78	gold quality
decidua	UBERON:0002450	74.69	gold quality
upper leg skin	UBERON:0004262	73.72	gold quality
oral cavity	UBERON:0000167	72.85	gold quality
rectum	UBERON:0001052	72.66	gold quality
Brodmann (1909) area 10	UBERON:0013541	71.07	gold quality
tongue squamous epithelium	UBERON:0006919	70.90	silver quality
colonic mucosa	UBERON:0000317	70.56	gold quality
skin of hip	UBERON:0001554	70.35	gold quality
mucosa of sigmoid colon	UBERON:0004993	70.24	gold quality
mammalian vulva	UBERON:0000997	70.10	gold quality
transverse colon	UBERON:0001157	69.88	gold quality
nasal cavity mucosa	UBERON:0001826	68.45	gold quality
penis	UBERON:0000989	68.11	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10596	yes	218.42
E-MTAB-6075	yes	23.91
E-ANND-3	yes	5.92

Regulation

Is transcription factor: yes

JASPAR motifs

Motif	Name	Family
MA0616.2	HES2	Hairy-related factors
MA0616.3	HES2	Hairy-related factors

JASPAR matrix evidence (PMIDs): PMID:8354270

miRNA regulators (miRDB)

70 targeting HES2, 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-5193	100.00	67.26	1744
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-6832-5P	99.58	64.82	1132
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
danio_rerio	hes2.2	ENSDARG00000068168
danio_rerio	hes2.1	ENSDARG00000074897
mus_musculus	Hes2	ENSMUSG00000028940
rattus_norvegicus	Hes2	ENSRNOG00000010490
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): HES1 (ENSG00000114315), BHLHE41 (ENSG00000123095), BHLHE40 (ENSG00000134107), HEY2 (ENSG00000135547), HES6 (ENSG00000144485), HEYL (ENSG00000163909), HEY1 (ENSG00000164683), HES3 (ENSG00000173673), HES7 (ENSG00000179111), HELT (ENSG00000187821), HES4 (ENSG00000188290), HES5 (ENSG00000197921)

Protein

Protein identifiers

Transcription factor HES-2 — Q9Y543 (reviewed: Q9Y543)

Alternative names: Class B basic helix-loop-helix protein 40, Hairy and enhancer of split 2

All UniProt accessions (3): Q9Y543, K7EJN2, K7EJQ0

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.

Tissue specificity. Expressed in placenta, pancreatic cancer, colon cancer with RER, cervical cancer, and in head and neck tumors.

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.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y543-1	1	yes
Q9Y543-2	2

RefSeq proteins (1): NP_061962* (*=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, chain 1, region of interest 1, short sequence motif 1, compositionally biased region 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y543-F1	74.47	0.18

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 106 (showing top): BENPORATH_ES_WITH_H3K27ME3, WHITE_NEUROBLASTOMA_WITH_1P36.3_DELETION, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_ANTERIOR_POSTERIOR_PATTERN_SPECIFICATION, LEI_HOXC8_TARGETS_UP, GOBP_REGULATION_OF_CELL_DEVELOPMENT, VECCHI_GASTRIC_CANCER_ADVANCED_VS_EARLY_UP, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, chr1p36, MEISSNER_NPC_HCP_WITH_H3K27ME3, MEISSNER_BRAIN_HCP_WITH_H3K27ME3, MIKKELSEN_NPC_HCP_WITH_H3K27ME3

GO Biological Process (6): regulation of transcription by RNA polymerase II (GO:0006357), anterior/posterior pattern specification (GO:0009952), regulation of neurogenesis (GO:0050767), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (7): 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), protein dimerization activity (GO:0046983), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), double-stranded DNA binding (GO:0003690)

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	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
DNA-templated transcription	2
regionalization	1
neurogenesis	1
regulation of nervous system development	1
regulation of cell development	1
negative regulation of DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
negative 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
protein binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
DNA binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

286 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HES2	ADGRL4	Q9HBW9	359
HES2	ZSWIM4	Q9H7M6	341
HES2	FERD3L	Q96RJ6	333
HES2	HES3	Q5TGS1	313
HES2	ASCL4	Q6XD76	312
HES2	SLC25A1	P53007	302
HES2	IGFL2	Q6UWQ7	302
HES2	ASCL3	Q9NQ33	293
HES2	BHLHE23	Q8NDY6	276
HES2	ATOH8	Q96SQ7	268
HES2	BNC1	Q01954	265
HES2	NIBAN1	Q9BZQ8	263
HES2	NEUROD4	Q9HD90	262
HES2	HEY2	Q9UBP5	260
HES2	TBC1D2	Q9BYX2	259

IntAct

0 interactions, top by confidence:

BioGRID (3): HES2 (Affinity Capture-MS), HES2 (Affinity Capture-MS), HES2 (Affinity Capture-RNA)

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

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

360 predictions. Top by Δscore:

Variant	Effect	Δscore
1:6419772:CCA:C	donor_loss	1.0000
1:6419773:CA:C	donor_loss	1.0000
1:6419775:C:CA	donor_loss	1.0000
1:6419239:A:AC	donor_gain	0.9900
1:6419240:C:CC	donor_gain	0.9900
1:6419601:GCTCA:G	donor_loss	0.9900
1:6419602:CTCA:C	donor_loss	0.9900
1:6419603:TCA:T	donor_loss	0.9900
1:6419604:CA:C	donor_loss	0.9900
1:6419605:ACCTC:A	donor_gain	0.9900
1:6419606:C:A	donor_loss	0.9900
1:6419606:CCTCC:C	donor_gain	0.9900
1:6419608:T:TA	donor_gain	0.9900
1:6419701:CT:C	acceptor_gain	0.9900
1:6419703:C:CC	acceptor_gain	0.9900
1:6419240:CGGGG:C	donor_gain	0.9800
1:6419352:C:CT	acceptor_gain	0.9800
1:6419609:C:A	donor_gain	0.9800
1:6419774:A:AC	donor_gain	0.9800
1:6419775:C:CC	donor_gain	0.9800
1:6419365:G:T	acceptor_gain	0.9700
1:6419605:ACCT:A	donor_gain	0.9700
1:6419606:CCTC:C	donor_gain	0.9700
1:6419235:A:AC	donor_gain	0.9600
1:6419236:C:CC	donor_gain	0.9600
1:6419352:C:T	acceptor_gain	0.9600
1:6419355:G:T	acceptor_gain	0.9600
1:6419698:AGGCT:A	acceptor_gain	0.9600
1:6419702:TCTG:T	acceptor_loss	0.9600
1:6419704:T:A	acceptor_loss	0.9600

AlphaMissense

1070 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:6419662:A:G	I29T	0.996
1:6419682:C:A	E22D	0.994
1:6419682:C:G	E22D	0.994
1:6419694:C:A	K18N	0.994
1:6419694:C:G	K18N	0.994
1:6419318:T:A	E55V	0.993
1:6419641:A:T	L36H	0.993
1:6419672:G:T	R26S	0.991
1:6419303:A:T	L60Q	0.988
1:6419679:C:A	K23N	0.987
1:6419679:C:G	K23N	0.987
1:6419683:T:A	E22V	0.987
1:6419662:A:C	I29S	0.986
1:6419641:A:G	L36P	0.985
1:6419662:A:T	I29N	0.985
1:6419684:C:T	E22K	0.985
1:6419665:C:G	R28P	0.984
1:6419669:C:G	A27P	0.984
1:6419696:T:C	K18E	0.982
1:6419666:G:T	R28S	0.979
1:6419282:A:G	L67P	0.978
1:6419658:G:C	N30K	0.977
1:6419658:G:T	N30K	0.977
1:6419303:A:G	L60P	0.976
1:6419650:A:T	L33Q	0.975
1:6419284:G:C	F66L	0.974
1:6419284:G:T	F66L	0.974
1:6419286:A:G	F66L	0.974
1:6419637:C:A	K37N	0.974
1:6419637:C:G	K37N	0.974

dbSNP variants (sampled 300 via entrez): RS1000107919 (1:6418651 A>C), RS1000281813 (1:6420191 G>A), RS1000583287 (1:6421305 A>G), RS1001640357 (1:6415698 C>G), RS1002287328 (1:6420282 G>A), RS1002444239 (1:6420021 C>T), RS1002505837 (1:6416991 C>T), RS1002805766 (1:6417713 C>G,T), RS1002880181 (1:6416344 G>A,T), RS1003185702 (1:6417979 C>T), RS1004855339 (1:6415497 A>G), RS1004925626 (1:6417637 G>T), RS1005362759 (1:6421162 C>T), RS1005854199 (1:6416550 G>A), RS1006574225 (1:6419678 G>A,C,T)

Disease associations

OMIM: gene MIM:609970 | 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

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects expression	3
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	3
Genistein	increases expression	3
sodium arsenite	decreases expression, increases expression	2
chloropicrin	decreases expression, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Calcitriol	increases expression, affects cotreatment	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Aflatoxin B1	increases expression	2
methyleugenol	increases expression	1
propionaldehyde	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
trichostatin A	increases expression	1
o,p’-DDT	increases expression	1
sulforaphane	decreases expression	1
butyraldehyde	increases expression	1
tobacco tar	decreases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
ICG 001	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
Zoledronic Acid	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Aldehydes	increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	increases expression	1

Clinical trials (associated diseases)

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