HEY1

Summary

HEY1 (hes related family bHLH transcription factor with YRPW motif 1, HGNC:4880) is a protein-coding gene on chromosome 8q21.13, encoding Hairy/enhancer-of-split related with YRPW motif protein 1 (Q9Y5J3). Transcriptional repressor which binds preferentially to the canonical E box sequence 5’-CACGTG-3'.

This gene encodes a nuclear protein belonging to the hairy and enhancer of split-related (HESR) family of basic helix-loop-helix (bHLH)-type transcriptional repressors. Expression of this gene is induced by the Notch and c-Jun signal transduction pathways. Two similar and redundant genes in mouse are required for embryonic cardiovascular development, and are also implicated in neurogenesis and somitogenesis. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 23462 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Disputed, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 57 total
• Transcription factor: yes — 36 downstream targets (CollecTRI)
• MANE Select transcript: NM_012258

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4880
Approved symbol	HEY1
Name	hes related family bHLH transcription factor with YRPW motif 1
Location	8q21.13
Locus type	gene with protein product
Status	Approved
Aliases	HESR-1, CHF2, HESR1, HRT-1, CHF-2, HERP2, bHLHb31
Ensembl gene	ENSG00000164683
Ensembl biotype	protein_coding
OMIM	602953
Entrez	23462

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 6 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000337919, ENST00000354724, ENST00000435063, ENST00000518733, ENST00000519075, ENST00000521111, ENST00000523531, ENST00000674160, ENST00000674177, ENST00000674192, ENST00000674295, ENST00000674358, ENST00000674418, ENST00000674439

RefSeq mRNA: 3 — MANE Select: NM_012258 NM_001040708, NM_001282851, NM_012258

CCDS: CCDS43749, CCDS6225

Canonical transcript exons

ENST00000354724 — 5 exons

Exon	Start	End
ENSE00001182152	79766651	79766732
ENSE00001288735	79767009	79767092
ENSE00001405005	79767575	79767767
ENSE00002102769	79764010	79765771
ENSE00003536892	79767219	79767294

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 99.11.

FANTOM5 (CAGE): breadth broad, TPM avg 6.1912 / max 151.1798, expressed in 895 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
93664	4.4242	714
93665	1.0938	425
93667	0.3676	168
93666	0.3056	150

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.11	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.71	gold quality
cranial nerve II	UBERON:0000941	98.63	gold quality
middle temporal gyrus	UBERON:0002771	98.51	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	97.73	gold quality
dorsal root ganglion	UBERON:0000044	97.63	gold quality
trigeminal ganglion	UBERON:0001675	97.16	gold quality
medial globus pallidus	UBERON:0002477	96.90	gold quality
visceral pleura	UBERON:0002401	96.86	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.60	gold quality
inferior olivary complex	UBERON:0002127	96.53	gold quality
globus pallidus	UBERON:0001875	96.43	gold quality
nasal cavity epithelium	UBERON:0005384	96.05	gold quality
pericardium	UBERON:0002407	95.99	gold quality
olfactory bulb	UBERON:0002264	95.50	gold quality
ventral tegmental area	UBERON:0002691	95.36	gold quality
medulla oblongata	UBERON:0001896	95.35	gold quality
lateral globus pallidus	UBERON:0002476	95.16	gold quality
trachea	UBERON:0003126	95.09	gold quality
entorhinal cortex	UBERON:0002728	95.04	gold quality
superior vestibular nucleus	UBERON:0007227	95.03	gold quality
tibia	UBERON:0000979	94.57	gold quality
pons	UBERON:0000988	94.47	gold quality
epithelium of bronchus	UBERON:0002031	94.08	gold quality
bronchus	UBERON:0002185	94.08	gold quality
ventricular zone	UBERON:0003053	93.99	gold quality
putamen	UBERON:0001874	93.86	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.84	gold quality
periodontal ligament	UBERON:0008266	93.67	gold quality
epithelium of nasopharynx	UBERON:0001951	93.66	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	1028.60
E-MTAB-8142	yes	833.25
E-GEOD-135922	yes	458.07
E-MTAB-8271	yes	256.93
E-HCAD-10	yes	254.35
E-CURD-112	yes	12.86
E-ANND-3	yes	8.69
E-MTAB-9388	yes	8.06
E-MTAB-10137	yes	7.33
E-MTAB-6678	no	2.43

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

36 targets.

Target	Regulation
ACAN	Repression
ACTA2	Repression
ACVR1
AR
ATXN1L
BMP2	Repression
CDKN1C	Repression
COL2A1	Repression
EFNB2
GATA4	Repression
GATA6	Repression
H2BC11
HES1
HES3
HES5
HEY1
ID1	Repression
IL6	Repression
KDR	Repression
MDM2
MEF2C	Repression
MYOG	Repression
NEURL1
NFATC1
NOTCH1
NOTCH2
NOTCH4
OCLN	Activation
PROX1	Repression
RBFOX2

JASPAR motifs

Motif	Name	Family
MA0823.1	HEY1	Hairy-related factors

JASPAR matrix evidence (PMIDs): PMID:22615585

Upstream regulators (CollecTRI, top): AR, DUX4, FOXC2, GATA5, GRHL3, HEY1, HEY2, HEYL, HIF1A, JUN, MAML1, MSX1, NOS3, NOTCH1, NOTCH3, NOTCH4, NR2F2, RBPJ, ROBO1, SMAD1, SMAD3, SMAD5

miRNA regulators (miRDB)

74 targeting HEY1, 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-3163	100.00	77.23	8605
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489

Literature-anchored findings (GeneRIF, showing 40)

• HESR-1 may be involved in the phenotypic changes that characterize the progression from EC proliferation and migration to network formation and quiescence (PMID:12453432)
• These results define a novel regulatory pathway linking the transcription factors c-Jun, HERP2, and GATA-1. (PMID:15314183)
• A similar gene in mouse regulates cardiovascular development (PMID:15680351)
• Hey1 is excluded from the nucleus in most human prostate cancers, raising the possibility that an abnormal Hey1 subcellular distribution may have a role in the aberrant hormonal responses observed in prostate cancer. (PMID:15684393)
• Hesr1 down-regulates DAT1 gene expression with the 3’ non-coding region, the negative regulations depend on bHLH and the Orange domain of the molecule, but not the YRPW motif. (PMID:15749835)
• HESR1 seems to inhibit the vessel-promoting effects of VEGF, shift endothelial cells from a proliferative state to a quiescent state, and restore normal vessel structures. (PMID:17028039)
• Declines in HEY1 are associated with pulmonary fibrosis and hypertension. (PMID:17496152)
• Present a novel mechanism by which a balance between Notch-1/-2/-4 signaling, via CBF-1, and HRT-1/-2 activity determines the expression of smooth muscle differentiation markers including actin. (PMID:18239137)
• Data imply a role for HEY1 in the progression of glioblastoma multiforme, and suggest that HEY1 may be a therapeutic target for glioblastoma patients. (PMID:18363832)
• Hey1 and Runx2 were shown to act synergistically in BMP9-induced osteogenic differentiation, and Runx2 expression significantly decreased in the absence of Hey1, suggesting that Runx2 may function downstream of Hey1 (PMID:18986983)
• Hey1 represses the KSHV RTA promoter, and mSin3A interacts with Hey1 and that this interaction is abolished in the presence of RTA. (PMID:19369342)
• Data show that HEY1 Leu94Met gene polymorphism converts HEY1 from an androgen receptor corepressor to an androgen receptor co-activator, and also abolishes HEY1-mediated activation of p53. (PMID:19802006)
• In transgenic mice Hey1 overexpression results in distinct progressive osteopenia and inhibition of osteoblasts ex vivo, an effect apparently dominant to a mild inhibition of osteoclasts. (PMID:19857617)
• Hey1 inhibits myogenesis by associating with and repressing expression of key myogenic targets. (PMID:19917614)
• In this study, we analyzed the effects of HESR1, -2, and -3 on DAT1 expression in human neuroblastoma SH-SY5Y cells (PMID:21290414)
• The novel HEY1-NCOA2 fusion appears to be the defining and diagnostic gene fusion in mesenchymal chondrosarcomas (PMID:22034177)
• Data suggest that HEs-1/Hey-1 transcriptional modulation of insulin degrading enzyme may impact amyloid beta metabolism by providing a functional link between Notch signaling and the amyloidogenic pathway. (PMID:22036964)
• These data further support a central role for Notch signalling in pancreatic cancer and suggest that nuclear expression of Notch3 and its target gene, HEY-1, merit validation in biomarker panels for diagnosis, prognosis and treatment efficacy. (PMID:23226563)
• The current study adds further support for the use of HEY1-NCOA2 fusion as a valid diagnostic marker for Mesenchymal chondrosarcoma (PMID:23252872)
• Data show that the periodontal ligament-derived mesenchymal stem cells (hPDLSCs) on a Jagged-1-modified surface had increased expression of Notch signaling target genes, Hes-1 and Hey-1, suggesting the involvement of Notch signaling in hPDLSCs. (PMID:23379739)
• HEY1 was overexpressed in colorectal cancer, and correlated with perineural and vascular invasion and lymph node metastasis as well as poorer prognosis. (PMID:23900217)
• The identification of HEY1-NCOA2 can be used as an auxiliary diagnostic tool to differentiate meningeal hemangiopericytoma from mesenchymal chondrosarcoma. (PMID:24124145)
• a new HRD1-associated membrane protein named HERP2, which is homologous to the previously identified HRD1 partner HERP1. Despite sequence homology, HERP2 is constitutively expressed in cells, whereas HERP1 is highly induced by ER stress. (PMID:24366871)
• PML degradation mechanism through Notch/Hey1-induced repression of the PML deubiquitinase USP11 involved in brain tumour pathogenesis (PMID:24487962)
• In prostate tumors, the overexpression of PTOV1 was associated with decreased expression of HEY1 and HES1, and this correlation was significant in metastatic lesions. (PMID:24684754)
• Overexpression of HEY1 and HEY2 in esophageal squamous cell carcinoma (ESCC) is correlated to different indices of poor prognosis, and it is extrapolated that such overexpression is important in progression and development of ESCC tumorigenesis. (PMID:25361534)
• MMP9 was a downstream effector of HEY1 that promotes the invasion of osteosarcoma cells. Knockdown of HEY1 decreased the expression of MMP9. (PMID:25742474)
• bone morphogenic proteins within the serum of cell culture medium are potent inducers of endothelial Hey1 and Hey2 gene expression within the first few hours after medium change (PMID:25799559)
• Expression of Hey1 induces translocation of FBXO45 into the nucleus. (PMID:26068074)
• Simulation of HEY1 Ser-68 phosphorylation prevents its interaction with p53, RPL11 and MDM2 and abolishes HEY1 migration to nucleolar caps upon ribosomal stress. Our findings uncover a novel mechanism for cross-talk between Notch signalling and nucleolar stress (PMID:27129302)
• HGF-induced FRA1 activation is associated with the fibrosis-dependent development of Hepatocellular Carcinoma. (PMID:27134167)
• Pancreatic involvement occurs in mesenchymal chondrosarcoma harboring the HEY1-NCOA2 gene fusion. (PMID:27544802)
• In HNSCC, the NOTCH4-HEY1 pathway is specifically upregulated, induces proliferation and cisplatin resistance, and promotes EMT. (PMID:29146722)
• Case Report:minute mesenchymal chondrosarcoma within an osteochondroma with HEY1-NCOA2 fusion. (PMID:29596896)
• findings suggest both NOTCH1-dependent and -independent HEY1 regulation, and imply a previously unrecognized prognostic role for HEY1 in HNSCC (PMID:29909892)
• HEY1 is negatively regulated by NFI family proteins and is associated with increased proliferation, decreased migration, and increased stem cell properties in glioblastoma cells. (PMID:30195713)
• Findings demonstrated that miR-769 suppressed the proliferation and invasion of CRC cells through targeting HEY1. (PMID:30565566)
• CAFs-derived MFAP5 promotes bladder cancer malignant behavior through NOTCH2/HEY1 signaling. (PMID:32293074)
• IMPAD1 functions as mitochondrial electron transport inhibitor that prevents ROS production and promotes lung cancer metastasis through the AMPK-Notch1-HEY1 pathway. (PMID:32417395)
• TWIST1 correlates with Notch signaling pathway to develop esophageal squamous cell carcinoma. (PMID:32712748)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	hey1	ENSDARG00000070538
mus_musculus	Hey1	ENSMUSG00000040289
rattus_norvegicus	Hey1	ENSRNOG00000062882
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), HES3 (ENSG00000173673), HES7 (ENSG00000179111), HELT (ENSG00000187821), HES4 (ENSG00000188290), HES5 (ENSG00000197921)

Protein

Protein identifiers

Hairy/enhancer-of-split related with YRPW motif protein 1 — Q9Y5J3 (reviewed: Q9Y5J3)

Alternative names: Cardiovascular helix-loop-helix factor 2, Class B basic helix-loop-helix protein 31, HES-related repressor protein 1, Hairy and enhancer of split-related protein 1, Hairy-related transcription factor 1

All UniProt accessions (6): A0A6I8PIY0, A0A6I8PRC2, A0A6I8PRS3, Q9Y5J3, A0A6I8PU82, E5RHK6

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor which binds preferentially to the canonical E box sequence 5’-CACGTG-3’. Downstream effector of Notch signaling required for cardiovascular development. Specifically required for the Notch-induced endocardial epithelial to mesenchymal transition, which is itself criticial for cardiac valve and septum development. May be required in conjunction with HEY2 to specify arterial cell fate or identity. Promotes maintenance of neuronal precursor cells and glial versus neuronal fate specification. Represses transcription by the cardiac transcriptional activators GATA4 and GATA6 and by the neuronal bHLH factors ASCL1/MASH1 and NEUROD4/MATH3. Involved in the regulation of liver cancer cells self-renewal.

Subunit / interactions. Self-associates. Interacts with HES1 and HEYL. Interacts with HDAC1, NCOR1 and SIN3A. Interacts with GATA4 and GATA6. Interacts with CCDC89/BOIP.

Subcellular location. Nucleus.

Tissue specificity. Expressed in the somitic mesoderm, the central nervous system, the kidney, the heart, nasal epithelium, and limbs.

Similarity. Belongs to the HEY family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y5J3-1	1	yes
Q9Y5J3-2	2

RefSeq proteins (2): NP_001035798, NP_036390* (*=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 (16 total): sequence conflict 3, helix 3, region of interest 3, domain 2, compositionally biased region 2, chain 1, short sequence motif 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2DB7	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5J3-F1	67.75	0.33

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-2122947	NOTCH1 Intracellular Domain Regulates Transcription
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-8940973	RUNX2 regulates osteoblast differentiation
R-HSA-9013508	NOTCH3 Intracellular Domain Regulates Transcription
R-HSA-9013695	NOTCH4 Intracellular Domain Regulates Transcription
R-HSA-9733709	Cardiogenesis

MSigDB gene sets: 375 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, REACTOME_SIGNALING_BY_NOTCH, GOBP_REGULATION_OF_VASCULOGENESIS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, LUCAS_HNF4A_TARGETS_DN, GOBP_VENTRICULAR_SEPTUM_MORPHOGENESIS, GOBP_HEART_TRABECULA_MORPHOGENESIS, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION

GO Biological Process (30): negative regulation of transcription by RNA polymerase II (GO:0000122), angiogenesis (GO:0001525), cardiac conduction system development (GO:0003161), aortic valve morphogenesis (GO:0003180), pulmonary valve morphogenesis (GO:0003184), atrioventricular valve formation (GO:0003190), endocardial cushion morphogenesis (GO:0003203), cardiac ventricle morphogenesis (GO:0003208), regulation of transcription by RNA polymerase II (GO:0006357), Notch signaling pathway (GO:0007219), anterior/posterior pattern specification (GO:0009952), dorsal aorta morphogenesis (GO:0035912), umbilical cord morphogenesis (GO:0036304), negative regulation of neuron differentiation (GO:0045665), negative regulation of Notch signaling pathway (GO:0045746), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of neurogenesis (GO:0050767), negative regulation of smooth muscle cell differentiation (GO:0051151), cardiac epithelial to mesenchymal transition (GO:0060317), heart trabecula formation (GO:0060347), cardiac septum morphogenesis (GO:0060411), ventricular septum morphogenesis (GO:0060412), labyrinthine layer blood vessel development (GO:0060716), arterial endothelial cell differentiation (GO:0060842), negative regulation of biomineral tissue development (GO:0070168), circulatory system development (GO:0072359), regulation of vasculogenesis (GO:2001212), regulation of DNA-templated transcription (GO:0006355), anatomical structure morphogenesis (GO:0009653)

GO Molecular Function (10): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription factor activity (GO:0003700), protein dimerization activity (GO:0046983), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Signaling by NOTCH1	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
RUNX2 regulates bone development	1
Signaling by NOTCH3	1
Signaling by NOTCH4	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
heart valve morphogenesis	2
heart morphogenesis	2
transcription cis-regulatory region binding	2
negative regulation of DNA-templated transcription	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
cardiac muscle tissue development	1
aortic valve development	1
pulmonary valve development	1
atrioventricular valve morphogenesis	1
heart valve formation	1
endocardial cushion development	1
mesenchyme morphogenesis	1
cardiac chamber morphogenesis	1
cardiac ventricle development	1
cell surface receptor signaling pathway	1
regionalization	1
dorsal aorta development	1
aorta morphogenesis	1
anatomical structure morphogenesis	1
umbilical cord development	1
neuron differentiation	1
negative regulation of cell differentiation	1
regulation of neuron differentiation	1
Notch signaling pathway	1
regulation of Notch signaling pathway	1
negative regulation of signal transduction	1
DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
neurogenesis	1
regulation of nervous system development	1
regulation of cell development	1
smooth muscle cell differentiation	1
negative regulation of muscle cell differentiation	1

Protein interactions and networks

STRING

1986 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HEY1	SKP1	P34991	989
HEY1	CUL1	Q13616	988
HEY1	JAG1	P78504	918
HEY1	NOTCH1	P46531	881
HEY1	DLL1	O00548	857
HEY1	NOTCH4	Q99466	841
HEY1	NRARP	Q7Z6K4	809
HEY1	RBPJ	Q06330	805
HEY1	DLL4	Q9NR61	792
HEY1	RUNX2	Q13950	788
HEY1	NOTCH3	Q9UM47	784
HEY1	NOTCH2	Q04721	782
HEY1	ID1	P41134	759
HEY1	CUL3	Q13618	755
HEY1	MAML1	Q92585	752

IntAct

42 interactions, top by confidence:

A	B	Type	Score
HEY2	HEY1	psi-mi:“MI:0915”(physical association)	0.670
HEY2	ARL10	psi-mi:“MI:0914”(association)	0.640
DAZAP2	HEY1	psi-mi:“MI:0915”(physical association)	0.560
PITX2	HEY1	psi-mi:“MI:0915”(physical association)	0.560
TENT5D	HEY1	psi-mi:“MI:0915”(physical association)	0.560
YTHDF1	HEY1	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-2	HEY1	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	HEY1	psi-mi:“MI:0915”(physical association)	0.560
PLEKHB2	HEY1	psi-mi:“MI:0915”(physical association)	0.560
	HEY1	psi-mi:“MI:0915”(physical association)	0.370
TNFSF14	HEY1	psi-mi:“MI:0915”(physical association)	0.370
SKIL	HEY1	psi-mi:“MI:0915”(physical association)	0.370
HEY1	SMAD3	psi-mi:“MI:0915”(physical association)	0.370
HEY1	PRKD2	psi-mi:“MI:0915”(physical association)	0.370
HEY1	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
LAPTM5	HEY1	psi-mi:“MI:0915”(physical association)	0.370
S100P	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
HECTD1	METTL15	psi-mi:“MI:0914”(association)	0.350
SPSB4	CCDC85C	psi-mi:“MI:0914”(association)	0.350
TLE1	TBX1	psi-mi:“MI:0914”(association)	0.350
HEY1	MYCBP2	psi-mi:“MI:0914”(association)	0.350
HEY1	HNRNPCL1	psi-mi:“MI:0914”(association)	0.350
HEY1	A2ML1	psi-mi:“MI:0914”(association)	0.350
PTBP3		psi-mi:“MI:0914”(association)	0.350
HEY1	DAZAP2	psi-mi:“MI:0915”(physical association)	0.000
PITX2	HEY1	psi-mi:“MI:0915”(physical association)	0.000
TENT5D	HEY1	psi-mi:“MI:0915”(physical association)	0.000
YTHDF1	HEY1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (171): HEY1 (Affinity Capture-MS), HES1 (Affinity Capture-MS), MYCBP2 (Affinity Capture-MS), FBXO45 (Affinity Capture-MS), SKP1 (Affinity Capture-MS), FBXO45 (Co-localization), DPF3 (Affinity Capture-Western), HEY1 (Affinity Capture-MS), TLE1 (Affinity Capture-Western), HEY1 (Reconstituted Complex), HES1 (Reconstituted Complex), HEY2 (Reconstituted Complex), HES1 (Reconstituted Complex), HEY2 (Reconstituted Complex), TP53 (Reconstituted Complex)

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

8 interactions.

A	Effect	B	Mechanism
HEY1	down-regulates	RBPJ	binding
RBPJ/NOTCH	“up-regulates quantity by expression”	HEY1	“transcriptional regulation”
DUX4	“up-regulates quantity by expression”	HEY1	“transcriptional regulation”
STK38	“up-regulates activity”	HEY1	phosphorylation
NOTCH1	“up-regulates quantity by expression”	HEY1	“transcriptional regulation”
HEY1	“down-regulates quantity by repression”	MEF2C	“transcriptional regulation”
HEY1	“down-regulates quantity by repression”	MYOG	“transcriptional regulation”
NOTCH	“up-regulates quantity by expression”	HEY1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	8
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

541 predictions. Top by Δscore:

Variant	Effect	Δscore
8:79765767:GTAAC:G	acceptor_gain	1.0000
8:79765768:TAAC:T	acceptor_gain	1.0000
8:79765769:AAC:A	acceptor_gain	1.0000
8:79765769:AACC:A	acceptor_loss	1.0000
8:79765770:AC:A	acceptor_gain	1.0000
8:79765770:ACCT:A	acceptor_loss	1.0000
8:79765771:CC:C	acceptor_gain	1.0000
8:79765772:C:CC	acceptor_gain	1.0000
8:79765772:C:T	acceptor_gain	1.0000
8:79765772:CTAA:C	acceptor_loss	1.0000
8:79765777:C:CT	acceptor_gain	1.0000
8:79765778:A:T	acceptor_gain	1.0000
8:79766649:ACCT:A	donor_loss	1.0000
8:79766650:C:CG	donor_loss	1.0000
8:79766654:T:A	donor_gain	1.0000
8:79766658:T:TA	donor_gain	1.0000
8:79766728:GATCC:G	acceptor_gain	1.0000
8:79766730:TCC:T	acceptor_gain	1.0000
8:79766730:TCCC:T	acceptor_loss	1.0000
8:79766731:CC:C	acceptor_gain	1.0000
8:79766731:CCC:C	acceptor_gain	1.0000
8:79766731:CCCTA:C	acceptor_loss	1.0000
8:79766732:CC:C	acceptor_gain	1.0000
8:79766733:C:CC	acceptor_gain	1.0000
8:79766733:C:CG	acceptor_loss	1.0000
8:79766733:C:T	acceptor_gain	1.0000
8:79766734:T:C	acceptor_loss	1.0000
8:79766995:A:AC	donor_gain	1.0000
8:79766996:C:CC	donor_gain	1.0000
8:79766996:CTTG:C	donor_gain	1.0000

AlphaMissense

1935 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:79765630:A:G	L158P	1.000
8:79765630:A:T	L158H	1.000
8:79765642:A:G	L154P	1.000
8:79765713:G:C	C130W	1.000
8:79765714:C:T	C130Y	1.000
8:79765715:A:G	C130R	1.000
8:79765722:A:C	F127L	1.000
8:79765722:A:T	F127L	1.000
8:79765723:A:G	F127S	1.000
8:79765724:A:G	F127L	1.000
8:79765726:C:T	G126E	1.000
8:79765727:C:G	G126R	1.000
8:79765727:C:T	G126R	1.000
8:79766680:A:G	L101P	1.000
8:79766680:A:T	L101Q	1.000
8:79766683:T:G	H100P	1.000
8:79766684:G:C	H100D	1.000
8:79766689:A:T	V98E	1.000
8:79766692:G:A	T97I	1.000
8:79766695:A:G	M96T	1.000
8:79766698:T:G	Q95P	1.000
8:79766701:A:C	L94R	1.000
8:79766701:A:G	L94P	1.000
8:79766701:A:T	L94Q	1.000
8:79766704:A:C	I93S	1.000
8:79766704:A:G	I93T	1.000
8:79766704:A:T	I93N	1.000
8:79766705:T:A	I93F	1.000
8:79766710:G:T	A91D	1.000
8:79766711:C:G	A91P	1.000

dbSNP variants (sampled 300 via entrez): RS1000005550 (8:79768775 A>T), RS1000072290 (8:79765897 G>C,T), RS1001212971 (8:79766549 C>A), RS1002326210 (8:79767809 C>T), RS1002763821 (8:79768011 C>G,T), RS1002964400 (8:79765392 G>A), RS1003554450 (8:79768737 A>C,G), RS1004076853 (8:79768773 G>A,T), RS1004108100 (8:79769040 C>G,T), RS1004901346 (8:79768928 T>A,C,G), RS1005533390 (8:79764998 C>A,T), RS1005606433 (8:79765289 G>A), RS1005833535 (8:79769489 C>T), RS1006369021 (8:79763525 C>G), RS1007254780 (8:79768438 C>G,T)

Disease associations

OMIM: gene MIM:602953 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart disease	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
congenital heart disease	Disputed	AD

Mondo (1): congenital heart disease (MONDO:0005453)

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST011584_3	Metastatic colorectal cancer survival in treatment with chemotherapy plus biologics	5.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0000714	survival time
EFO:1001480	metastatic colorectal cancer

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation, affects expression, decreases expression	5
sodium arsenite	decreases expression, increases abundance, increases expression	4
Silicon Dioxide	decreases expression, increases expression	4
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	4
MRK 003	decreases expression	3
Cyclosporine	increases expression	3
entinostat	decreases expression, affects cotreatment	2
Arsenic Trioxide	affects methylation, decreases expression	2
Benzo(a)pyrene	increases expression	2
Cisplatin	affects cotreatment, decreases expression, increases expression	2
Lipopolysaccharides	decreases reaction, increases expression, affects reaction	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Tretinoin	increases expression	2
Tunicamycin	decreases expression	2
Thapsigargin	decreases expression	2
bisphenol F	increases expression	1
N-((3,5-difluorophenyl)acetyl)alanyl-2-phenylglycine-1,1-dimethylethyl ester	affects expression, decreases reaction	1
sotorasib	affects cotreatment, increases expression	1
propionaldehyde	increases expression	1
baicalein	increases expression, decreases reaction	1
bisphenol A	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	increases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
pyrvinium	decreases expression, decreases reaction	1
loliolide	increases expression	1
cupric oxide	increases expression	1
baicalin	increases expression, decreases reaction	1

Cellosaurus cell lines

10 cell lines: 5 cancer cell line, 3 embryonic stem cell, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A2P3	SEES3-1V human HEY1, clone1	Embryonic stem cell	Male
CVCL_A2P4	SEES3-1V human HEY1, clone2	Embryonic stem cell	Male
CVCL_A2P5	SEES3-1V human HEY1, clone3	Embryonic stem cell	Male
CVCL_B2YN	Abcam HEK293T HEY1 KO	Transformed cell line	Female
CVCL_B8HD	Abcam HCT 116 HEY1 KO	Cancer cell line	Male
CVCL_B8WR	Abcam MCF-7 HEY1 KO	Cancer cell line	Female
CVCL_B9JM	Abcam A-549 HEY1 KO	Cancer cell line	Male
CVCL_D7RA	Ubigene A-549 HEY1 KO	Cancer cell line	Male
CVCL_D9G6	Ubigene HEK293 HEY1 KO	Transformed cell line	Female
CVCL_E0E9	Ubigene HeLa HEY1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE