BHLHE40

Summary

BHLHE40 (basic helix-loop-helix family member e40, HGNC:1046) is a protein-coding gene on chromosome 3p26.1, encoding Class E basic helix-loop-helix protein 40 (O14503). Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes.

This gene encodes a basic helix-loop-helix protein expressed in various tissues. The encoded protein can interact with ARNTL or compete for E-box binding sites in the promoter of PER1 and repress CLOCK/ARNTL’s transactivation of PER1. This gene is believed to be involved in the control of circadian rhythm and cell differentiation.

Source: NCBI Gene 8553 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 73 total — 1 pathogenic, 1 likely-pathogenic
• Transcription factor: yes — 44 downstream targets (CollecTRI)
• MANE Select transcript: NM_003670

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1046
Approved symbol	BHLHE40
Name	basic helix-loop-helix family member e40
Location	3p26.1
Locus type	gene with protein product
Status	Approved
Aliases	DEC1, SHARP2, Clast5
Ensembl gene	ENSG00000134107
Ensembl biotype	protein_coding
OMIM	604256
Entrez	8553

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 retained_intron

ENST00000256495, ENST00000460806, ENST00000467610, ENST00000931070

RefSeq mRNA: 1 — MANE Select: NM_003670 NM_003670

CCDS: CCDS2565

Canonical transcript exons

ENST00000256495 — 5 exons

Exon	Start	End
ENSE00000912410	4979962	4980031
ENSE00000912411	4980301	4980408
ENSE00000997170	4982836	4985323
ENSE00001841521	4979437	4979798
ENSE00003613596	4981392	4981515

Expression profiles

Bgee: expression breadth ubiquitous, 302 present calls, max score 99.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 110.2641 / max 2444.6386, expressed in 1819 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35092	104.6950	1818
35093	2.4183	1063
35094	2.3362	807
35097	0.5826	264
35096	0.2321	103

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
saphenous vein	UBERON:0007318	99.33	gold quality
vena cava	UBERON:0004087	99.32	gold quality
lower esophagus mucosa	UBERON:0035834	99.27	gold quality
type B pancreatic cell	CL:0000169	99.13	gold quality
pharyngeal mucosa	UBERON:0000355	99.10	gold quality
esophagus mucosa	UBERON:0002469	99.08	gold quality
synovial joint	UBERON:0002217	99.04	gold quality
pericardium	UBERON:0002407	99.02	gold quality
esophagus squamous epithelium	UBERON:0006920	98.86	gold quality
cauda epididymis	UBERON:0004360	98.84	gold quality
mucosa of stomach	UBERON:0001199	98.78	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.75	gold quality
penis	UBERON:0000989	98.67	gold quality
gall bladder	UBERON:0002110	98.62	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.50	gold quality
epithelium of esophagus	UBERON:0001976	98.48	gold quality
mammary duct	UBERON:0001765	98.45	gold quality
trachea	UBERON:0003126	98.44	gold quality
mucosa of urinary bladder	UBERON:0001259	98.42	gold quality
skin of leg	UBERON:0001511	98.38	gold quality
epithelium of mammary gland	UBERON:0003244	98.28	gold quality
skin of abdomen	UBERON:0001416	98.25	gold quality
tibial artery	UBERON:0007610	98.19	gold quality
popliteal artery	UBERON:0002250	98.18	gold quality
adenohypophysis	UBERON:0002196	98.17	gold quality
squamous epithelium	UBERON:0006914	98.12	gold quality
gingival epithelium	UBERON:0001949	98.07	gold quality
body of tongue	UBERON:0011876	98.07	gold quality
gingiva	UBERON:0001828	98.05	gold quality
renal medulla	UBERON:0000362	97.98	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-6108	yes	569.66
E-ENAD-21	yes	526.16
E-GEOD-76312	yes	500.82
E-ENAD-20	yes	344.53
E-CURD-89	yes	167.73
E-CURD-114	yes	70.80
E-MTAB-9467	yes	39.48
E-MTAB-6678	yes	21.97
E-CURD-122	yes	11.01
E-GEOD-130148	yes	8.80
E-MTAB-8410	yes	8.52
E-CURD-46	yes	5.94
E-GEOD-106540	no	1117.54
E-MTAB-7303	no	144.70
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

44 targets.

Target	Regulation
BDNF
BHLHE40	Repression
BHLHE41	Repression
BIRC5	Activation
BMAL1
CCND1	Unknown
CDH15	Unknown
CENPX
CLOCK
COL10A1	Activation
COL2A1	Activation
CRY1
CXCL8
CYP3A4
CYP51A1
CYP7A1
DELEC1
FAS	Repression
ID1	Repression
IFNG	Activation
IHH	Activation
IL10
IL2	Unknown
IL2RA	Activation
MLH1
MYOD1
NR1H4	Repression
PCK2	Repression
PER1	Repression
PER2	Repression

JASPAR motifs

Motif	Name	Family
MA0464.2	BHLHE40	Hairy-related factors
MA0464.3	BHLHE40	Hairy-related factors

JASPAR matrix evidence (PMIDs): PMID:15186484

Upstream regulators (CollecTRI, top): ARNT, BHLHE40, BHLHE41, BMAL1, BMAL2, CLOCK, E2F1, EPAS1, HIF1A, NEUROD1, NFKB, NR1H2, NR1H3, RARA, RELA, RORA, SOX9, TP53, USF1, VDR

miRNA regulators (miRDB)

147 targeting BHLHE40, 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-1277-5P	100.00	73.95	5056
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595

Literature-anchored findings (GeneRIF, showing 40)

• hypoxia-induced gene in pancreatic cancer cell lines (PMID:11688991)
• DEC1-mediated anti-apoptosis is achieved by blocking apoptotic pathways initiated via the mitochondria. The results functionally distinguish DEC1 from other bHLH proteins and directly link this factor to oncogenesis. (PMID:12119049)
• DEC1 and DEC2 may play a crucial role in the adaptation to hypoxia (PMID:12354771)
• DEC1 is the first transcription factor that can promote both chondrogenic differentiation and terminal differentiation (PMID:12384505)
• Dec1 and Dec2 are regulators of the mammalian molecular clock, and form a fifth clock-gene family. (PMID:12397359)
• DEC1-mediated repression on the expression of DEC2 provides an important mechanism that these transcription factors regulate the cellular function of members within the same class (PMID:12624110)
• Findings suggest that the basic region of DEC1 participates in the transcriptional regulation through a protein-protein interaction with BMAL1 and DNA binding to the E-box. (PMID:15560782)
• STRA13 interacts with the cell cycle-associated transcription factor MSP58. (PMID:15719173)
• STRA13 was expressed in epithelial cells of normal and neoplastic tissues mostly in the nucleus. Intense cytoplasmic STRA13 immunoreactivity was characteristic of myoepithelial and differentiated squamous epithelial cells and their neoplastic counterparts (PMID:15994878)
• DEC1 expression is found in the majority of 1p-aberrant oligodendroglial neoplasms; its immunohistochemical detection does not correlate with tisue hypoxia in this type of primary brain tumor. (PMID:16136500)
• DEC1 selectively increases the expression of survivin among antiapoptotic proteins. (PMID:16462771)
• These findings suggest that Dec1 modulates osteogenic differentiation of mesenchymal stem cells by inducing the expression of several, but not all, bone-related genes. (PMID:16487626)
• link between HIF-1 and STAT1 reveals a previously unknown role of STRA13 in hypoxia and carcinogenesis (PMID:16878149)
• differentiated embryo-chondrocyte expressed gene 1 downregulates hypoxia-inducible factor 1alpha at both mRNA and protein levels at hypoxia in lung adenocarcinoma cells (PMID:17376295)
• DEC1 is induced by the p53 family and DNA damage in a p53-dependent manner. p53 family proteins bind to, and activate, the promoter of the DEC1 gene. (PMID:18025081)
• A multi-locus interaction between rs6442925 in the 5’ upstream of BHLHB2, rs1534891 in CSNK1E, and rs534654 near the 3’ end of the CLOCK gene, however, is significantly associated with bipolar disorder (PMID:18228528)
• MLH1 is transcriptionally repressed by the hypoxia-inducible transcription factors, DEC1 and DEC2. (PMID:18345027)
• DEC1, along with DEC2, plays a role in the finer regulation and robustness of the molecular clock CLOCK/BMAL1 (PMID:18411297)
• Identificaiton of BHLHB2 as a potential novel mediator of insulin transcriptional action in human skeletal muscle. (PMID:19590847)
• The hypoxia-regulated transcription factor DEC1 and its expression in gastric cancer are reported. (PMID:19624270)
• Hypoxia-inducible BHLHB2 expression is a novel independent prognostic marker in pancreatic cancer patients and indicates increased chemosensitivity towards gemcitabine. (PMID:20863812)
• Study conclude that DeltaNp63 is a novel target of DEC1 and HDAC2 and modulates the efficacy of HDAC inhibitors in growth suppression and keratinocyte differentiation. (PMID:21317427)
• DEC1 has pro-apoptotic effects on the paclitaxel-induced apoptosis in human breast cancer MCF-7 cells. (PMID:21327324)
• DEC1 is expressed in the cytoplasm of hepatocytes and because nuclear DEC1 expression is decreased with decreasing differentiation status ofhepatocellular carcinoma (HCC), nuclear DEC1 might be a marker of HCC differentiation (PMID:21528084)
• DEC1 expression is correlated with HIF-1alpha protein in gastric cancer cell line. (PMID:21779800)
• findings suggested that posttranslational modification of DEC1 in the form of SUMOylation may serve as a key factor that regulates the function of DEC1 in vivo (PMID:21829689)
• Expression of BHLHB2 is inhibited by PML-RARalpha through binding to its promoter in acute promyeloid leukemia. (PMID:21867633)
• IL-1beta can induce DEC1 and HIF-1alpha protein levels in gingival epithelial cells. We also demonstrate that the increase in DEC1 protein subsequently is followed by Akt phosphorylation. (PMID:22644784)
• Marginal zone B cells activated by hepatitis C virus undergo functional exhaustion associated with BCR signaling defects and overexpression of a key antiproliferative gene, and may subsequently become terminally spent CD21(low) B cells. (PMID:22678901)
• DEC1 controls the response of p53-dependent cell survival vs. cell death to a stress signal through MIC-1 (PMID:22723347)
• findings suggest that the repression of CYP3A4 by IL-6 is achieved through increasing the DEC1 expression in human hepatocytes, the increased DEC1 binds to the CCCTGC sequence in the promoter of CYP3A4 to form CCCTGC-DEC1 complex (PMID:22728071)
• These findings suggest that DEC1 plays an important role in the regulation of these EMT-related factors in pancreatic cancer. (PMID:22825629)
• DEC1 overexpression in precursor lesions of esophageal squamous cell carcinoma is a protective mechanism (PMID:22844531)
• SUMO modification of Stra13 is required for repression of cyclin D1 expression and cellular growth arrest (PMID:22905217)
• Staircase-style fluctuations in the BHLHE40 mRNA accumulation relate to the short half-life of the gene’s mRNA of 0.9h. (PMID:23220548)
• Loss of DEC1 may promote tumor progression in non-small-cell lung cancer through upregulation of cyclin D1 (PMID:23423709)
• Studied DEC1 & claudin-1 in invasive breast ductal carcinomas;found DEC1 elevated in invasive breast ductal carcinoma. DEC1 knockdown led to the enhanced expression of claudin-1 at both the mRNA and protein levels in breast cancer cell lines. (PMID:23426649)
• DEC1 level was positively correlated with HIF-1alpha and Ki67 expression in gastric cancer. (PMID:23445622)
• Sunitinib treatment performance could be attributable to TIS, depending on p53/Dec1 activation. (PMID:23578198)
• Study demonstrates that DEC1 is involved in osteogenesis. (PMID:24397494)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	bhlhe40	ENSDARG00000004060
mus_musculus	Bhlhe40	ENSMUSG00000030103
rattus_norvegicus	Bhlhe40	ENSRNOG00000007152
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), HEY2 (ENSG00000135547), HES6 (ENSG00000144485), HEYL (ENSG00000163909), HEY1 (ENSG00000164683), HES3 (ENSG00000173673), HES7 (ENSG00000179111), HELT (ENSG00000187821), HES4 (ENSG00000188290), HES5 (ENSG00000197921)

Protein

Protein identifiers

Class E basic helix-loop-helix protein 40 — O14503 (reviewed: O14503)

Alternative names: Class B basic helix-loop-helix protein 2, Differentially expressed in chondrocytes protein 1, Enhancer-of-split and hairy-related protein 2, Stimulated by retinoic acid gene 13 protein

All UniProt accessions (2): O14503, Q6IB83

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes. Acts as the negative limb of a novel autoregulatory feedback loop (DEC loop) which differs from the one formed by the PER and CRY transcriptional repressors (PER/CRY loop). Both these loops are interlocked as it represses the expression of PER1/2 and in turn is repressed by PER1/2 and CRY1/2. Represses the activity of the circadian transcriptional activator: CLOCK-BMAL1|BMAL2 heterodimer by competing for the binding to E-box elements (5’-CACGTG-3’) found within the promoters of its target genes. Negatively regulates its own expression and the expression of DBP and BHLHE41/DEC2. Acts as a corepressor of RXR and the RXR-LXR heterodimers and represses the ligand-induced RXRA and NR1H3/LXRA transactivation activity. May be involved in the regulation of chondrocyte differentiation via the cAMP pathway. Represses the transcription of NR0B2 and attentuates the transactivation of NR0B2 by the CLOCK-BMAL1 complex. Drives the circadian rhythm of blood pressure through transcriptional repression of ATP1B1 in the cardiovascular system.

Subunit / interactions. Homodimer. Heterodimer with BHLHE41/DEC2. Interacts with TCF3/E47. Interacts with ubiquitin-conjugating enzyme UBE2I/UBC9. Interacts with HDAC1, SUMO1, RXRA and BMAL1.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in cartilage, spleen, intestine, lung, and to a lesser extent in heart, brain, liver, muscle and stomach.

Post-translational modifications. Ubiquitinated; which may lead to proteasomal degradation. Sumoylation inhibits its ubiquitination and promotes its negative regulation of the CLOCK-BMAL1 heterodimer transcriptional activator activity.

RefSeq proteins (1): NP_003661* (*=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 (22 total): mutagenesis site 7, cross-link 6, region of interest 3, domain 2, modified residue 2, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14503-F1	60.60	0.17

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 (8): 167, 279, 279, 279, 288, 235, 383, 159

Mutagenesis-validated functional residues (7):

Position	Phenotype
56	no loss of repressor activity against nr0b2.
57	no effect on its interaction with bmal1 or its repressor activity against the clock-bmal1 heterodimer. significant reduc
58	loss of repressor activity against nr0b2.
65	loss of interaction with bmal1 and e-box binding. significant reduction in its repressor activity against the clock-bmal
78–79	abolishes rxra repression.
159	partial loss of sumoylation. complete loss of sumoylation; when associated with r-279.
279	partial loss of sumoylation. complete loss of sumoylation; when associated with r-159.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1368108	BMAL1:CLOCK,NPAS2 activates circadian expression
R-HSA-9931510	Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes
R-HSA-400253

MSigDB gene sets: 665 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_CIRCADIAN_RHYTHM, BROWNE_HCMV_INFECTION_6HR_DN, WWTAAGGC_UNKNOWN, HARRIS_HYPOXIA, BOYAULT_LIVER_CANCER_SUBCLASS_G56_DN, AMIT_DELAYED_EARLY_GENES, LU_IL4_SIGNALING, BASSO_B_LYMPHOCYTE_NETWORK, GOBP_PHOTOPERIODISM, AMIT_EGF_RESPONSE_60_HELA, CMYB_01, MENSE_HYPOXIA_UP, DITTMER_PTHLH_TARGETS_UP, TATTATA_MIR374

GO Biological Process (11): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), circadian rhythm (GO:0007623), anterior/posterior pattern specification (GO:0009952), circadian regulation of gene expression (GO:0032922), regulation of circadian rhythm (GO:0042752), entrainment of circadian clock by photoperiod (GO:0043153), negative regulation of DNA-templated transcription (GO:0045892), regulation of neurogenesis (GO:0050767), rhythmic process (GO:0048511)

GO Molecular Function (15): 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), DNA-binding transcription factor activity (GO:0003700), protein domain specific binding (GO:0019904), protein homodimerization activity (GO:0042803), bHLH transcription factor binding (GO:0043425), MRF binding (GO:0043426), protein heterodimerization activity (GO:0046982), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), E-box binding (GO:0070888), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), protein dimerization activity (GO:0046983)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), cytoplasm (GO:0005737), nuclear body (GO:0016604)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Circadian clock	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
DNA-templated transcription	2
regulation of gene expression	2
circadian rhythm	2
protein binding	2
protein dimerization activity	2
DNA-binding transcription factor binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
regulation of RNA biosynthetic process	1
rhythmic process	1
regionalization	1
regulation of biological process	1
photoperiodism	1
entrainment of circadian clock	1
negative regulation of RNA biosynthetic process	1
neurogenesis	1
regulation of nervous system development	1
regulation of cell development	1
biological_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
transcription cis-regulatory region binding	1
transcription regulator activity	1
identical protein binding	1
bHLH transcription factor binding	1
RNA polymerase II cis-regulatory region sequence-specific DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1760 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BHLHE40	BMAL1	O00327	965
BHLHE40	CRY1	Q16526	957
BHLHE40	PER2	O15055	936
BHLHE40	NR1D1	P20393	927
BHLHE40	NPAS2	Q99743	921
BHLHE40	PER3	P56645	917
BHLHE40	NFIL3	Q16649	902
BHLHE40	NR1D2	Q14995	890
BHLHE40	RORA	P35397	869
BHLHE40	RORB	Q92753	856
BHLHE40	CLOCK	O15516	845
BHLHE40	CRY2	Q49AN0	833
BHLHE40	CSNK1E	P49674	830
BHLHE40	RORC	P51449	796
BHLHE40	GPKOW	Q92917	772

IntAct

316 interactions, top by confidence:

A	B	Type	Score
BHLHE40	SMYD1	psi-mi:“MI:0915”(physical association)	0.830
RHOBTB3	BHLHE40	psi-mi:“MI:0915”(physical association)	0.780
BHLHE40	RHOBTB3	psi-mi:“MI:0915”(physical association)	0.780
BHLHE40	TP53	psi-mi:“MI:0914”(association)	0.730
BHLHE40	TP53	psi-mi:“MI:0915”(physical association)	0.730
WHR1	BHLHE40	psi-mi:“MI:0915”(physical association)	0.720
BHLHE40	VAC14	psi-mi:“MI:0915”(physical association)	0.720
BHLHE40	MAGED1	psi-mi:“MI:0915”(physical association)	0.720
AANAT	BHLHE40	psi-mi:“MI:0915”(physical association)	0.720
BHLHE40	NAA50	psi-mi:“MI:0915”(physical association)	0.720
BHLHE40	WHR1	psi-mi:“MI:0915”(physical association)	0.720
NAA50	BHLHE40	psi-mi:“MI:0915”(physical association)	0.720
MAGED1	BHLHE40	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (142): USP21 (Affinity Capture-Western), USP17L9P (Affinity Capture-Western), BHLHE40 (Affinity Capture-Western), BHLHE40 (Affinity Capture-Western), BHLHE40 (Biochemical Activity), BHLHE40 (Biochemical Activity), BTRC (Affinity Capture-Western), BHLHE40 (Two-hybrid), BHLHE40 (Two-hybrid), BHLHE40 (Two-hybrid), BHLHE40 (Two-hybrid), BHLHE40 (Two-hybrid), BHLHE40 (Two-hybrid), BHLHE40 (Two-hybrid), BHLHE40 (Two-hybrid)

ESM2 similar proteins: A0A287BDC1, A8YXY8, B1AXD8, B3F209, B3KU38, B5DF41, O00287, O14503, O15079, O35185, O54972, P03966, P04198, P12755, P18444, P26014, Q0D2I5, Q25C79, Q2KJ58, Q3MHV6, Q3UR85, Q50H33, Q53H80, Q5BL57, Q5EA15, Q5FWN7, Q5RAI7, Q60591, Q60698, Q61976, Q63379, Q68FF7, Q6GQB5, Q6ZWB6, Q7ZY70, Q8BXL9, Q8CEG5, Q8CI08, Q8N228, Q8ND83

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

11 interactions.

A	Effect	B	Mechanism
UBE2I	“down-regulates quantity by destabilization”	BHLHE40	polyubiquitination
CSNK1A1	“down-regulates quantity by destabilization”	BHLHE40	phosphorylation
USP17L2	“up-regulates quantity by stabilization”	BHLHE40	deubiquitination
SCF-betaTRCP	“down-regulates quantity by destabilization”	BHLHE40	ubiquitination
NR1H2	“up-regulates quantity by expression”	BHLHE40	“transcriptional regulation”
NR1H3	“up-regulates quantity by expression”	BHLHE40	“transcriptional regulation”
CLOCK/BMAL1	“up-regulates quantity by expression”	BHLHE40	“transcriptional regulation”
BHLHE41	“down-regulates quantity by repression”	BHLHE40	“transcriptional regulation”
BHLHE40	“down-regulates quantity by repression”	BHLHE40	“transcriptional regulation”
BHLHE40	“down-regulates quantity by repression”	BHLHE41	“transcriptional regulation”
BHLHE40	“down-regulates quantity by repression”	PER2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 69 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
Keratinization	8	10.4×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	61
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3777759	Single allele	Pathogenic
635936	Single allele	Likely pathogenic

SpliceAI

357 predictions. Top by Δscore:

Variant	Effect	Δscore
3:4979961:GGAT:G	acceptor_gain	1.0000
3:4980027:GCAAG:G	donor_gain	1.0000
3:4980028:CAAGG:C	donor_loss	1.0000
3:4980030:AGG:A	donor_loss	1.0000
3:4980031:GGT:G	donor_loss	1.0000
3:4980032:G:GG	donor_gain	1.0000
3:4980033:T:G	donor_loss	1.0000
3:4980296:TGCAG:T	acceptor_loss	1.0000
3:4980297:GCAGG:G	acceptor_loss	1.0000
3:4980299:A:AG	acceptor_gain	1.0000
3:4980299:AG:A	acceptor_gain	1.0000
3:4980300:G:GC	acceptor_loss	1.0000
3:4980300:G:GG	acceptor_gain	1.0000
3:4980300:GG:G	acceptor_gain	1.0000
3:4980300:GGA:G	acceptor_gain	1.0000
3:4980404:TTACA:T	donor_gain	1.0000
3:4980405:TACA:T	donor_gain	1.0000
3:4980406:ACA:A	donor_gain	1.0000
3:4980407:CA:C	donor_gain	1.0000
3:4980409:G:GG	donor_gain	1.0000
3:4980410:T:G	donor_loss	1.0000
3:4980413:G:GG	donor_gain	1.0000
3:4981388:CCAG:C	acceptor_loss	1.0000
3:4981389:CAG:C	acceptor_loss	1.0000
3:4981390:A:AG	acceptor_gain	1.0000
3:4981390:AGA:A	acceptor_loss	1.0000
3:4981391:G:A	acceptor_loss	1.0000
3:4981391:G:GA	acceptor_gain	1.0000
3:4981391:GA:G	acceptor_gain	1.0000
3:4981391:GAC:G	acceptor_gain	1.0000

AlphaMissense

2678 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:4980319:C:G	H57D	1.000
3:4980326:T:C	L59P	1.000
3:4980329:T:A	I60N	1.000
3:4980331:G:A	E61K	1.000
3:4980332:A:T	E61V	1.000
3:4980333:G:C	E61D	1.000
3:4980333:G:T	E61D	1.000
3:4980334:A:G	K62E	1.000
3:4980335:A:T	K62I	1.000
3:4980336:A:C	K62N	1.000
3:4980336:A:T	K62N	1.000
3:4980341:G:C	R64T	1.000
3:4980342:A:C	R64S	1.000
3:4980342:A:T	R64S	1.000
3:4980343:C:A	R65S	1.000
3:4980344:G:C	R65P	1.000
3:4980350:G:C	R67P	1.000
3:4980353:T:A	I68N	1.000
3:4980353:T:C	I68T	1.000
3:4980353:T:G	I68S	1.000
3:4980355:A:G	N69D	1.000
3:4980357:C:A	N69K	1.000
3:4980357:C:G	N69K	1.000
3:4980361:T:C	C71R	1.000
3:4980363:C:G	C71W	1.000
3:4980365:T:A	I72N	1.000
3:4980365:T:G	I72S	1.000
3:4980374:T:A	L75Q	1.000
3:4980374:T:C	L75P	1.000
3:4980374:T:G	L75R	1.000

dbSNP variants (sampled 300 via entrez): RS1000038262 (3:4977472 A>G), RS1000070841 (3:4977706 T>C), RS1000380056 (3:4985675 A>G), RS1000716525 (3:4984274 A>G), RS1001785054 (3:4985028 GAAT>G), RS1001794233 (3:4979720 T>A,C), RS1001837553 (3:4984654 C>T), RS1001975460 (3:4978601 G>A), RS1002072625 (3:4978820 C>T), RS1002130728 (3:4980090 A>G), RS1002529792 (3:4978693 T>A), RS1002732022 (3:4981207 CACACACACACAT>C), RS1003194072 (3:4980996 T>C,G), RS1003760238 (3:4980838 C>A,T), RS1003860164 (3:4981631 T>C)

Disease associations

OMIM: gene MIM:604256 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001261_1	Corneal structure	2.000000e-06
GCST003268_5	Psoriasis vulgaris	3.000000e-07
GCST005411_3	Thrombin-activatable fibrinolysis inhibitor activation peptide	4.000000e-07
GCST007932_76	Medication use (thyroid preparations)	4.000000e-10
GCST009597_318	Multiple sclerosis	2.000000e-06
GCST012170_10	Cognitive function in longevity	6.000000e-06
GCST012227_354	Hip circumference adjusted for BMI	5.000000e-09
GCST90011900_83	Serum alkaline phosphatase levels	3.000000e-08
GCST90020028_1293	Hip circumference adjusted for BMI	3.000000e-13

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:1001494	psoriasis vulgaris
EFO:0009933	Thyroid preparation use measurement
EFO:0008354	cognitive function measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, affects cotreatment, increases expression, affects expression	9
Estradiol	decreases reaction, affects cotreatment, increases expression, decreases expression	6
trichostatin A	affects cotreatment, increases expression, affects expression	4
Oxygen	increases expression	4
bisphenol A	decreases expression, increases expression, affects cotreatment	3
sodium arsenite	affects cotreatment, increases abundance, decreases expression	3
Formaldehyde	increases expression	3
Tretinoin	affects expression, affects cotreatment, increases expression	3
Cyclosporine	increases expression	3
methylmercuric chloride	decreases expression, increases expression	2
arsenite	decreases methylation, decreases expression, increases abundance	2
afimoxifene	increases expression, affects reaction	2
cobaltous chloride	affects cotreatment, increases expression, decreases reaction	2
nickel sulfate	increases expression	2
cadmium sulfate	affects cotreatment, increases expression, decreases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Arsenic Trioxide	increases expression, affects cotreatment	2
Vorinostat	decreases expression, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Ethanol	affects cotreatment, increases expression, decreases expression, increases abundance	2
Arsenic	decreases response to substance, affects cotreatment, decreases expression, increases abundance	2
Cisplatin	affects expression, increases expression	2
Folic Acid	affects cotreatment, increases expression	2
Indomethacin	increases expression, affects cotreatment, decreases expression	2
Mercury	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Asbestos, Crocidolite	increases expression	2
Cadmium Chloride	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
Particulate Matter	increases abundance, increases expression, affects cotreatment, decreases expression	2

Cellosaurus cell lines

7 cell lines: 3 embryonic stem cell, 3 cancer cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A0I1	SEES3-1V human BHLHE40, clone1	Embryonic stem cell	Male
CVCL_A0I2	SEES3-1V human BHLHE40, clone2	Embryonic stem cell	Male
CVCL_A0I3	SEES3-1V human BHLHE40, clone3	Embryonic stem cell	Male
CVCL_B8C0	Abcam HCT 116 BHLHE40 KO	Cancer cell line	Male
CVCL_B9E5	Abcam A-549 BHLHE40 KO	Cancer cell line	Male
CVCL_D2E0	Abcam MCF-7 BHLHE40 KO	Cancer cell line	Female
CVCL_HD65	HaCaT BHLHE40 (-/-)	Spontaneously immortalized cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice