NHLH1

Summary

NHLH1 (nescient helix-loop-helix 1, HGNC:7817) is a protein-coding gene on chromosome 1q23.2, encoding Helix-loop-helix protein 1 (Q02575). May serve as DNA-binding protein and may be involved in the control of cell-type determination, possibly within the developing nervous system.

The helix-loop-helix (HLH) proteins are a family of putative transcription factors, some of which have been shown to play an important role in growth and development of a wide variety of tissues and species. Four members of this family have been clearly implicated in tumorigenesis via their involvement in chromosomal translocations in lymphoid tumors: MYC (MIM 190080), LYL1 (MIM 151440), E2A (MIM 147141), and SCL (MIM 187040).

Source: NCBI Gene 4807 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 17 total
• MANE Select transcript: NM_005598

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7817
Approved symbol	NHLH1
Name	nescient helix-loop-helix 1
Location	1q23.2
Locus type	gene with protein product
Status	Approved
Aliases	NSCL, NSCL1, bHLHa35
Ensembl gene	ENSG00000171786
Ensembl biotype	protein_coding
OMIM	162360
Entrez	4807

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000302101

RefSeq mRNA: 1 — MANE Select: NM_005598 NM_005598

CCDS: CCDS1204

Canonical transcript exons

ENST00000302101 — 2 exons

Exon	Start	End
ENSE00001166315	160367071	160367337
ENSE00001171263	160370557	160372846

Expression profiles

Bgee: expression breadth ubiquitous, 110 present calls, max score 97.18.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.4766 / max 498.7455, expressed in 155 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
6120	1.4029	155
6121	0.0737	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	97.18	gold quality
embryo	UBERON:0000922	88.75	gold quality
ventricular zone	UBERON:0003053	81.08	gold quality
endometrium epithelium	UBERON:0004811	78.92	gold quality
type B pancreatic cell	CL:0000169	76.74	gold quality
tongue squamous epithelium	UBERON:0006919	75.53	gold quality
olfactory bulb	UBERON:0002264	74.79	gold quality
CA1 field of hippocampus	UBERON:0003881	73.98	gold quality
buccal mucosa cell	CL:0002336	72.73	gold quality
diaphragm	UBERON:0001103	72.23	gold quality
endothelial cell	CL:0000115	71.09	gold quality
epithelial cell of pancreas	CL:0000083	70.94	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	68.47	gold quality
hair follicle	UBERON:0002073	67.98	gold quality
epithelium of nasopharynx	UBERON:0001951	67.92	gold quality
cerebellar vermis	UBERON:0004720	67.45	gold quality
inferior olivary complex	UBERON:0002127	67.36	gold quality
choroid plexus epithelium	UBERON:0003911	66.55	gold quality
gingival epithelium	UBERON:0001949	65.81	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	64.99	gold quality
cortical plate	UBERON:0005343	64.56	gold quality
thymus	UBERON:0002370	64.41	gold quality
Brodmann (1909) area 46	UBERON:0006483	64.13	gold quality
nasal cavity epithelium	UBERON:0005384	63.91	gold quality
cervix squamous epithelium	UBERON:0006922	63.70	gold quality
Brodmann (1909) area 10	UBERON:0013541	63.41	gold quality
mucosa of paranasal sinus	UBERON:0005030	63.14	gold quality
myocardium	UBERON:0002349	62.71	gold quality
superficial temporal artery	UBERON:0001614	62.62	gold quality
putamen	UBERON:0001874	61.92	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-10485	yes	919.83
E-HCAD-5	yes	890.11
E-MTAB-6911	yes	862.51
E-GEOD-75140	yes	281.26
E-ANND-3	no	1.11

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
ID2
LMO4
NDN
SHH
SLC13A4

JASPAR motifs

Motif	Name	Family
MA0048.1	NHLH1	Tal-related
MA0048.2	NHLH1	Tal-related
MA0048.3	NHLH1	Tal-related
MA1938.1	ERF::NHLH1	Ets-related::Tal-related
MA1938.2	ERF::NHLH1	Ets-related::Tal-related

JASPAR matrix evidence (PMIDs): PMID:8289804, PMID:9488464

Upstream regulators (CollecTRI, top): ATOH7, GLI1, ISL1, NEUROG3

miRNA regulators (miRDB)

113 targeting NHLH1, 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-5692A	100.00	74.40	6850
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-370-5P	99.78	66.81	706
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6764-5P	99.75	67.89	2304

Literature-anchored findings (GeneRIF, showing 3)

• expression of NSCL-1 and NSCL-2 in the developing central and peripheral nervous system, most likely in developing neurons. (PMID:1328219)
• This study identified that CGPs was found to significantly correlate with the differential expression and methylation of genes encoding nescient helix-loop-helix 1. (PMID:25243493)
• The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression (PMID:27149122)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nhlh1	ENSMUSG00000051251
rattus_norvegicus	Nhlh1	ENSRNOG00000005166

Paralogs (4): LYL1 (ENSG00000104903), TAL1 (ENSG00000162367), NHLH2 (ENSG00000177551), TAL2 (ENSG00000186051)

Protein

Protein identifiers

Helix-loop-helix protein 1 — Q02575 (reviewed: Q02575)

Alternative names: Class A basic helix-loop-helix protein 35, Nescient helix loop helix 1

All UniProt accessions (2): Q02575, Q5T203

UniProt curated annotations — full annotation on UniProt →

Function. May serve as DNA-binding protein and may be involved in the control of cell-type determination, possibly within the developing nervous system.

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein.

Subcellular location. Nucleus.

RefSeq proteins (1): NP_005589* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR040238	TAL-like	Family

Pfam: PF00010

UniProt features (6 total): compositionally biased region 3, chain 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02575-F1	78.33	0.54

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 112 (showing top): TGCACTT_MIR519C_MIR519B_MIR519A, GCANCTGNY_MYOD_Q6, TAL1ALPHAE47_01, GGGTGGRR_PAX4_03, GTGCCTT_MIR506, MYOD_01, TGCTGAY_UNKNOWN, OUELLET_CULTURED_OVARIAN_CANCER_INVASIVE_VS_LMP_DN, WTGAAAT_UNKNOWN, MYOD_Q6, SCHLOSSER_SERUM_RESPONSE_DN, MODULE_497, AACTTT_UNKNOWN, VDR_Q3, E12_Q6

GO Biological Process (4): regulation of transcription by RNA polymerase II (GO:0006357), central nervous system development (GO:0007417), cell differentiation (GO:0030154), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (8): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), 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 activator activity, RNA polymerase II-specific (GO:0001228), protein dimerization activity (GO:0046983), sequence-specific double-stranded DNA binding (GO:1990837), 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	3
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
regulation of DNA-templated transcription	1
nervous system development	1
system development	1
cellular developmental process	1
positive regulation of DNA-templated transcription	1
transcription cis-regulatory region binding	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
protein binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

976 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NHLH1	LHX9	Q9NQ69	701
NHLH1	NEUROD1	Q13562	597
NHLH1	TBR1	Q16650	547
NHLH1	LMO2	P25791	545
NHLH1	CIC	Q96RK0	512
NHLH1	EOMES	O95936	503
NHLH1	KLF7	O75840	484
NHLH1	HOXB2	P10913	477
NHLH1	NEUROD2	Q15784	465
NHLH1	HES3	Q5TGS1	462
NHLH1	INSM1	Q01101	461
NHLH1	EMX2	Q04743	460
NHLH1	SOX11	P35716	457
NHLH1	PDGFA	P04085	425
NHLH1	NR2F1	P10589	424
NHLH1	NOG	Q13253	424

IntAct

15 interactions, top by confidence:

A	B	Type	Score
NHLH1	CCT7	psi-mi:“MI:0915”(physical association)	0.560
NHLH1	CENPP	psi-mi:“MI:0915”(physical association)	0.560
NHLH1		psi-mi:“MI:0915”(physical association)	0.560
HIVEP1	NHLH1	psi-mi:“MI:0915”(physical association)	0.520
PSME2	NHLH1	psi-mi:“MI:0915”(physical association)	0.370
NHLH1	INO80E	psi-mi:“MI:0915”(physical association)	0.370
NHLH1	CLPX	psi-mi:“MI:0914”(association)	0.350
NHLH1	IGF2BP3	psi-mi:“MI:2364”(proximity)	0.270
CCT7	NHLH1	psi-mi:“MI:0915”(physical association)	0.000
CENPP	NHLH1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (93): PIM1 (Two-hybrid), CENPP (Two-hybrid), LMO2 (Two-hybrid), TCF3 (Two-hybrid), NHLH1 (Two-hybrid), CENPP (Two-hybrid), xlmo1 (Two-hybrid), NHLH1 (Affinity Capture-Western), TCF3 (Proximity Label-MS), HIVEP1 (Proximity Label-MS), TCF12 (Proximity Label-MS), IGF2BP3 (Proximity Label-MS), NOP56 (Proximity Label-MS), KMT2D (Proximity Label-MS), NKRF (Proximity Label-MS)

ESM2 similar proteins: O35437, O43680, O60682, O88940, O93507, O96004, P22091, P24899, P27792, P48985, P57100, P59101, P70447, P70562, P70595, P70660, P70661, P79782, P97832, Q02346, Q02575, Q02576, Q02577, Q12870, Q15672, Q5E9S3, Q60539, Q60756, Q64124, Q64221, Q64279, Q7JGP2, Q7RTU7, Q8BGW3, Q8MI03, Q8MI06, Q8MIB5, Q8MIB9, Q8MID5, Q8MIE7

Diamond homologs: A8E5T6, B6VQA1, O13125, O13126, O16867, O35437, O42202, O42606, O43680, O57598, O60682, O73615, O73823, O88940, O93507, O96004, O96642, P13903, P17542, P22091, P24899, P26687, P46581, P48985, P48987, P57100, P57101, P57102, P59101, P61295, P61296, P70661, P79765, P79782, P97831, P97832, Q02575, Q02576, Q02577, Q0VCE2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NEUROG3	“up-regulates quantity by expression”	NHLH1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	15
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

177 predictions. Top by Δscore:

Variant	Effect	Δscore
1:160370555:A:AG	acceptor_gain	0.9800
1:160370556:G:GG	acceptor_gain	0.9800
1:160370552:TTCA:T	acceptor_loss	0.9700
1:160370553:TCA:T	acceptor_loss	0.9700
1:160370554:CA:C	acceptor_loss	0.9700
1:160370555:A:AT	acceptor_loss	0.9700
1:160367333:TCTAG:T	donor_loss	0.9500
1:160367334:CTAG:C	donor_loss	0.9500
1:160367335:TAGGT:T	donor_loss	0.9500
1:160367336:AGG:A	donor_loss	0.9500
1:160367337:GG:G	donor_loss	0.9500
1:160367338:G:GA	donor_loss	0.9500
1:160367339:T:A	donor_loss	0.9500
1:160370555:AG:A	acceptor_gain	0.9400
1:160370556:GG:G	acceptor_gain	0.9400
1:160370556:GGC:G	acceptor_gain	0.8600
1:160367340:A:C	donor_loss	0.8500
1:160370554:CAGG:C	acceptor_gain	0.8500
1:160370553:TCAGG:T	acceptor_gain	0.8200
1:160370556:GGCTT:G	acceptor_gain	0.8100
1:160372145:G:GC	acceptor_gain	0.8000
1:160367610:G:GT	donor_gain	0.7700
1:160370209:T:TA	acceptor_gain	0.7700
1:160370555:AGG:A	acceptor_gain	0.7600
1:160367334:C:G	donor_gain	0.7400
1:160370188:C:G	acceptor_gain	0.7400
1:160370611:C:G	donor_gain	0.7400
1:160370210:C:A	acceptor_gain	0.7200
1:160372141:CCTTG:C	acceptor_gain	0.7100
1:160372142:CTTG:C	acceptor_gain	0.7100

AlphaMissense

835 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:160370957:T:C	Y76H	1.000
1:160370958:A:G	Y76C	1.000
1:160370969:C:G	H80D	1.000
1:160370981:G:A	E84K	1.000
1:160370982:A:C	E84A	1.000
1:160370982:A:T	E84V	1.000
1:160370983:A:C	E84D	1.000
1:160370983:A:T	E84D	1.000
1:160370984:C:A	R85S	1.000
1:160370985:G:C	R85P	1.000
1:160370990:C:A	R87S	1.000
1:160370990:C:T	R87C	1.000
1:160371002:T:C	F91L	1.000
1:160371004:C:A	F91L	1.000
1:160371004:C:G	F91L	1.000
1:160371014:T:C	F95L	1.000
1:160371016:C:A	F95L	1.000
1:160371016:C:G	F95L	1.000
1:160371024:T:C	L98P	1.000
1:160371033:T:C	L101P	1.000
1:160371036:T:A	L102Q	1.000
1:160371038:C:A	P103T	1.000
1:160371038:C:T	P103S	1.000
1:160371039:C:A	P103H	1.000
1:160371039:C:G	P103R	1.000
1:160371066:C:A	S112Y	1.000
1:160371066:C:T	S112F	1.000
1:160371068:A:C	K113Q	1.000
1:160371068:A:G	K113E	1.000
1:160371069:A:T	K113M	1.000

dbSNP variants (sampled 300 via entrez): RS1000824034 (1:160367810 G>C,T), RS1001505943 (1:160372224 C>A,T), RS1001820521 (1:160365577 G>T), RS1001915294 (1:160365652 G>A), RS1001983410 (1:160367141 G>A), RS1002053129 (1:160372589 G>A), RS1002120132 (1:160366984 G>A,C,T), RS1002277927 (1:160366762 A>C), RS1002325254 (1:160366059 C>T), RS1002618472 (1:160369133 TTCTACTTTCTGTTTC>T), RS1004409074 (1:160365303 A>G), RS1004970089 (1:160368536 T>C), RS1005000957 (1:160368673 T>A), RS1005630456 (1:160365734 T>G), RS1005663185 (1:160366251 T>C)

Disease associations

OMIM: gene MIM:162360 | 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)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11265375	NHLH1		0.00	0

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, decreases methylation, increases expression	2
Valproic Acid	affects expression, decreases expression	2
aristolochic acid I	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
azoxystrobin	decreases expression	1
pyrimidifen	decreases expression	1
licochalcone B	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Antimycin A	decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Carbamazepine	affects expression	1
Diethylhexyl Phthalate	decreases expression	1
Lead	affects expression	1
Rotenone	increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Lithium Chloride	decreases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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