BARHL2

Summary

BARHL2 (BarH like homeobox 2, HGNC:954) is a protein-coding gene on chromosome 1p22.2, encoding BarH-like 2 homeobox protein (Q9NY43). Potential regulator of neural basic helix-loop-helix genes.

Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including generation of neurons; positive regulation of macromolecule biosynthetic process; and regulation of axon extension. Predicted to be located in chromatin. Predicted to be active in nucleus. Implicated in oral squamous cell carcinoma. Biomarker of colorectal cancer; oral squamous cell carcinoma; and stomach cancer.

Source: NCBI Gene 343472 — RefSeq curated summary.

At a glance

• GWAS associations: 26
• Clinical variants (ClinVar): 61 total
• MANE Select transcript: NM_020063

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:954
Approved symbol	BARHL2
Name	BarH like homeobox 2
Location	1p22.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000143032
Ensembl biotype	protein_coding
OMIM	605212
Entrez	343472

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000370445

RefSeq mRNA: 1 — MANE Select: NM_020063 NM_020063

CCDS: CCDS730

Canonical transcript exons

ENST00000370445 — 3 exons

Exon	Start	End
ENSE00001338960	90714531	90714756
ENSE00001452735	90711539	90712624
ENSE00001452736	90716571	90717302

Expression profiles

Bgee: expression breadth broad, 26 present calls, max score 90.35.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0379 / max 16.2662, expressed in 18 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13211	0.0379	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellum	UBERON:0002037	90.35	gold quality
cerebellar cortex	UBERON:0002129	90.27	gold quality
cerebellar hemisphere	UBERON:0002245	90.24	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.58	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.06	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	74.47	silver quality
right testis	UBERON:0004534	57.90	gold quality
testis	UBERON:0000473	57.43	gold quality
left testis	UBERON:0004533	56.39	gold quality
hypothalamus	UBERON:0001898	48.22	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	43.42	gold quality
ventricular zone	UBERON:0003053	40.85	silver quality
cortical plate	UBERON:0005343	40.09	gold quality
brain	UBERON:0000955	39.26	gold quality
sural nerve	UBERON:0015488	38.78	gold quality
substantia nigra	UBERON:0002038	38.55	gold quality
lower esophagus mucosa	UBERON:0035834	37.49	gold quality
amygdala	UBERON:0001876	37.25	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
temporal lobe	UBERON:0001871	37.16	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
apex of heart	UBERON:0002098	35.42	gold quality
right coronary artery	UBERON:0001625	34.51	gold quality
mucosa of stomach	UBERON:0001199	34.43	gold quality
mucosa of transverse colon	UBERON:0004991	34.34	gold quality
frontal cortex	UBERON:0001870	33.49	gold quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
bone marrow	UBERON:0002371	32.88	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	471.04
E-ANND-3	no	0.82

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
AVPR2

JASPAR motifs

Motif	Name	Family
MA0635.1	BARHL2	NK
MA0635.2	BARHL2	NK

JASPAR matrix evidence (PMIDs): PMID:18585359

Upstream regulators (CollecTRI, top): ATOH1

miRNA regulators (miRDB)

36 targeting BARHL2, 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-10401-5P	99.99	65.79	948
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-4704-3P	98.28	69.33	1300

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	barhl2	ENSDARG00000104361
mus_musculus	Barhl2	ENSMUSG00000034384
rattus_norvegicus	Barhl2	ENSRNOG00000002117
drosophila_melanogaster	B-H2	FBGN0004854
drosophila_melanogaster	B-H1	FBGN0011758
caenorhabditis_elegans		WBGENE00000451
caenorhabditis_elegans		WBGENE00000452

Paralogs (3): BARX2 (ENSG00000043039), BARHL1 (ENSG00000125492), BARX1 (ENSG00000131668)

Protein

Protein identifiers

BarH-like 2 homeobox protein — Q9NY43 (reviewed: Q9NY43)

All UniProt accessions (1): Q9NY43

UniProt curated annotations — full annotation on UniProt →

Function. Potential regulator of neural basic helix-loop-helix genes.

Subcellular location. Nucleus.

Similarity. Belongs to the BAR homeobox family.

RefSeq proteins (1): NP_064447* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR020479	HD_metazoa	Domain
IPR052145	Mediator/Homeobox_domain	Family

Pfam: PF00046

UniProt features (14 total): compositionally biased region 6, helix 3, region of interest 3, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
8PMF	X-RAY DIFFRACTION	0.95
8PMN	X-RAY DIFFRACTION	1.3
8PNA	X-RAY DIFFRACTION	1.45
8PM7	X-RAY DIFFRACTION	1.7
8PMC	X-RAY DIFFRACTION	1.85
8R7F	X-RAY DIFFRACTION	1.98
8PNC	X-RAY DIFFRACTION	2.05
8PMV	X-RAY DIFFRACTION	2.1
8PM5	X-RAY DIFFRACTION	2.4
8PN4	X-RAY DIFFRACTION	2.6
8R7Z	X-RAY DIFFRACTION	3.26

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NY43-F1	62.10	0.15

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 116 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_GROWTH, GOBP_NEUROGENESIS, CHX10_01, EFC_Q6, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, OCT1_03, WTGAAAT_UNKNOWN, GRE_C, RYTAAWNNNTGAY_UNKNOWN, GOBP_REGULATION_OF_CELL_SIZE

GO Biological Process (11): cell fate determination (GO:0001709), neuron migration (GO:0001764), regulation of transcription by RNA polymerase II (GO:0006357), regulation of axon extension (GO:0030516), amacrine cell differentiation (GO:0035881), positive regulation of translation (GO:0045727), regulation of DNA-templated transcription (GO:0006355), nervous system development (GO:0007399), neuron differentiation (GO:0030182), cell fate commitment (GO:0045165), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (7): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), 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
cellular developmental process	2
generation of neurons	2
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
cell differentiation	2
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cell fate commitment	1
cell migration	1
regulation of developmental growth	1
axon extension	1
regulation of extent of cell growth	1
neural retina development	1
central nervous system neuron differentiation	1
translation	1
regulation of translation	1
positive regulation of gene expression	1
positive regulation of protein metabolic process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
system development	1
positive regulation of DNA-templated transcription	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
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
transcription regulator activity	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1140 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BARHL2	FOXN4	Q96NZ1	632
BARHL2	PTF1A	Q7RTS3	624
BARHL2	BHLHE22	Q8NFJ8	575
BARHL2	NEUROD4	Q9HD90	508
BARHL2	ISL1	P20663	500
BARHL2	ATOH7	Q8N100	478
BARHL2	LHX5	Q9H2C1	461
BARHL2	POU4F2	Q12837	453
BARHL2	PBX3	P40426	433
BARHL2	LHX9	Q9NQ69	431
BARHL2	ZNF608	Q9ULD9	418
BARHL2	TFAP2A	P05549	412
BARHL2	NFIA	Q12857	412
BARHL2	LHX1	P48742	405
BARHL2	NOVA2	Q9UNW9	404

IntAct

7 interactions, top by confidence:

A	B	Type	Score
REL	BARHL2	psi-mi:“MI:0915”(physical association)	0.560
BARHL2	REL	psi-mi:“MI:0915”(physical association)	0.560
PLEKHF2	BARHL2	psi-mi:“MI:0915”(physical association)	0.560
BARHL2	PLEKHF2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (2): BARHL2 (Two-hybrid), PLEKHF2 (Two-hybrid)

ESM2 similar proteins: A0A8V0YY16, A0JPN1, A7MB54, A8MTJ6, O35762, O42115, O57601, O88181, O95096, P09065, P23683, P28356, P31311, P31315, P32443, P39020, P42581, P42586, P43697, P48031, P49640, P50222, P50476, P52951, P52954, P52955, P78426, P81067, P81068, P97334, Q14549, Q14774, Q1KKY1, Q1XID0, Q2NKI2, Q2VL76, Q2VL80, Q4V5A3, Q5SQQ9, Q60554

Diamond homologs: A0JPN1, A1YG85, A5PKG8, A6NJ46, A6NMT0, A7MB54, A9L937, B0VXK3, D2KQB0, E7FDX5, M0R6D8, O08686, O13023, O35762, O42365, O43364, O43711, O55144, O88181, O93366, O93367, O93590, P0C1T1, P10035, P14652, P14837, P20009, P28468, P31245, P31246, P31261, P31314, P42583, P42584, P43120, P43345, P43688, P50219, P52945, P52950

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	59
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

581 predictions. Top by Δscore:

Variant	Effect	Δscore
1:90714528:TA:T	donor_loss	1.0000
1:90714530:CCTG:C	donor_gain	1.0000
1:90716566:CTCA:C	donor_loss	1.0000
1:90716567:TCAC:T	donor_loss	1.0000
1:90716568:CACCG:C	donor_loss	1.0000
1:90716569:A:AC	donor_gain	1.0000
1:90716569:AC:A	donor_gain	1.0000
1:90716570:C:CC	donor_gain	1.0000
1:90716570:C:G	donor_loss	1.0000
1:90716570:CC:C	donor_gain	1.0000
1:90716570:CCG:C	donor_gain	1.0000
1:90713570:CGTA:C	acceptor_gain	0.9900
1:90713573:A:C	acceptor_gain	0.9900
1:90714529:A:AC	donor_gain	0.9900
1:90714530:C:CC	donor_gain	0.9900
1:90714755:CC:C	acceptor_gain	0.9900
1:90714756:CC:C	acceptor_gain	0.9900
1:90714761:C:CT	acceptor_gain	0.9900
1:90716570:CCGT:C	donor_gain	0.9900
1:90716570:CCGTG:C	donor_gain	0.9900
1:90712623:TCCT:T	acceptor_loss	0.9800
1:90712625:C:CC	acceptor_gain	0.9800
1:90712626:T:C	acceptor_loss	0.9800
1:90714187:CTGG:C	donor_gain	0.9800
1:90714529:ACCTG:A	donor_gain	0.9800
1:90714530:CCT:C	donor_gain	0.9800
1:90714530:CCTGC:C	donor_gain	0.9800
1:90714540:TGG:T	donor_gain	0.9800
1:90714754:TCCC:T	acceptor_loss	0.9800
1:90714755:CCCT:C	acceptor_loss	0.9800

AlphaMissense

2538 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:90712581:C:G	A299P	1.000
1:90712583:A:G	L298P	1.000
1:90712583:A:T	L298Q	1.000
1:90712586:A:G	L297S	1.000
1:90712589:T:A	E296V	1.000
1:90712590:C:T	E296K	1.000
1:90712592:A:G	L295P	1.000
1:90712595:C:T	G294D	1.000
1:90712596:C:G	G294R	1.000
1:90712602:C:G	A292P	1.000
1:90712606:C:A	Q290H	1.000
1:90712606:C:G	Q290H	1.000
1:90712607:T:G	Q290P	1.000
1:90712610:C:G	R289P	1.000
1:90712611:G:A	R289W	1.000
1:90712611:G:C	R289G	1.000
1:90712612:C:A	K288N	1.000
1:90712612:C:G	K288N	1.000
1:90712613:T:A	K288M	1.000
1:90712613:T:G	K288T	1.000
1:90712614:T:C	K288E	1.000
1:90712614:T:G	K288Q	1.000
1:90712615:C:A	W287C	1.000
1:90712615:C:G	W287C	1.000
1:90712616:C:G	W287S	1.000
1:90712617:A:G	W287R	1.000
1:90712617:A:T	W287R	1.000
1:90712618:C:A	K286N	1.000
1:90712618:C:G	K286N	1.000
1:90712619:T:A	K286M	1.000

dbSNP variants (sampled 300 via entrez): RS1000039509 (1:90711931 T>C), RS1000559086 (1:90711787 T>C), RS1001097037 (1:90715329 T>C), RS1001159235 (1:90712838 C>T), RS1001444998 (1:90713080 G>A), RS1001528534 (1:90715623 T>C), RS1001997116 (1:90712449 G>A), RS1002337210 (1:90719199 A>C,G,T), RS1002351437 (1:90712260 G>A,C,T), RS1003045950 (1:90715791 G>T), RS1003162277 (1:90715471 C>A), RS1003256238 (1:90714040 G>A), RS1003500299 (1:90718895 C>A,G), RS1003555677 (1:90711697 A>T), RS1003617798 (1:90711143 C>A)

Disease associations

OMIM: gene MIM:605212 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST004077_3	Cognitive function	3.000000e-08
GCST005316_298	Intelligence (MTAG)	2.000000e-12
GCST005830_48	Hand grip strength	4.000000e-08
GCST006041_41	Major depressive disorder	3.000000e-06
GCST006920_3	Regular attendance at a gym or sports club	2.000000e-06
GCST006921_1	Regular attendance at a pub or social club	2.000000e-13
GCST006922_3	Regular attendance at a religious group	2.000000e-10
GCST007323_1	Risk-taking tendency (4-domain principal component model)	3.000000e-09
GCST007324_85	Adventurousness	4.000000e-09
GCST007325_117	General risk tolerance (MTAG)	2.000000e-11
GCST007326_101	Number of sexual partners	9.000000e-12
GCST007327_160	Smoking status (ever vs never smokers)	5.000000e-11
GCST007335_1	Age at first sexual intercourse	1.000000e-08
GCST007565_127	Morning person	4.000000e-21
GCST007576_21	Chronotype	4.000000e-21
GCST007603_25	Smoking initiation	1.000000e-08
GCST008595_8	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	3.000000e-13
GCST008810_66	Smoking initiation (ever regular vs never regular)	7.000000e-10
GCST009523_2	Household income	2.000000e-09
GCST009524_155	Household income (MTAG)	3.000000e-12
GCST009524_237	Household income (MTAG)	2.000000e-15
GCST010002_362	Refractive error	1.000000e-30
GCST010988_245	Adult body size	2.000000e-09
GCST011703_38	Smoking initiation	7.000000e-11
GCST011704_2	Smoking status (current vs never)	2.000000e-08
GCST90000047_11	Age at first sexual intercourse	2.000000e-24

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0006941	grip strength measurement
EFO:0009592	social interaction measurement
EFO:0008579	risk-taking behaviour
EFO:0004318	smoking behavior
EFO:0009749	age at first sexual intercourse measurement
EFO:0008328	chronotype measurement
EFO:0005670	smoking initiation
EFO:0004784	self reported educational attainment
EFO:0009695	household income
EFO:0006527	smoking status measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
arsenite	increases methylation	1
butyraldehyde	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Dimethyl Sulfoxide	affects expression	1
Plant Extracts	affects cotreatment, decreases expression	1
1-Methyl-4-phenylpyridinium	decreases expression	1
Aflatoxin B1	decreases methylation	1
Copper Sulfate	increases expression	1
Acrylamide	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A0G3	SEES3-1V human BARHL2, clone1	Embryonic stem cell	Male
CVCL_A0G4	SEES3-1V human BARHL2, clone2	Embryonic stem cell	Male
CVCL_A0G5	SEES3-1V human BARHL2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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