ASCL4

Summary

ASCL4 (achaete-scute family bHLH transcription factor 4, HGNC:24311) is a protein-coding gene on chromosome 12q23.3, encoding Achaete-scute homolog 4 (Q6XD76). Could be a transcriptional regulator involved in skin development.

Basic helix-loop-helix transcription factors, such as ASCL4, are essential for the determination of cell fate and the development and differentiation of numerous tissues (Jonsson et al., 2004 [PubMed 15475265]).

Source: NCBI Gene 121549 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 42 total
• GTEx eGene: eQTL in 1 tissue, sQTL in 0 (q < 0.05)
• Constraint (gnomAD): pLI 0.13 (intermediate), LOEUF 1.92 (unconstrained)
• MANE Select transcript: NM_203436

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24311
Approved symbol	ASCL4
Name	achaete-scute family bHLH transcription factor 4
Location	12q23.3
Locus type	gene with protein product
Status	Approved
Aliases	HASH4, bHLHa44
Ensembl gene	ENSG00000187855
Ensembl biotype	protein_coding
OMIM	609155
Entrez	121549

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

MANE Select: ENST00000342331

ENST00000342331

RefSeq mRNA: 1 — MANE Select: NM_203436 NM_203436

CCDS: CCDS31894

Canonical transcript exons

ENST00000342331 — 1 exons

Exon	Start	End
ENSE00001376797	107774704	107776644

Expression profiles

Bgee: expression breadth broad, 11 present calls, max score 75.79.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0343 / max 60.7341, expressed in 1 samples.

Highest expression (Bgee): cerebellar vermis, thymus, quadriceps femoris, sural nerve, tonsil.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ASCL4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 1 tissue and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

1 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Spleen	eqtl	1.1e-05	+0.44	12:107883805:T:G

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
206882	0.0343	1

Top tissues by expression

showing 100 of 123 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	75.79	gold quality
thymus	UBERON:0002370	68.77	silver quality
quadriceps femoris	UBERON:0001377	65.07	gold quality
sural nerve	UBERON:0015488	50.21	gold quality
tonsil	UBERON:0002372	43.58	gold quality
colonic epithelium	UBERON:0000397	41.48	gold quality
lymph node	UBERON:0000029	40.42	silver quality
vermiform appendix	UBERON:0001154	38.62	silver quality
hindlimb stylopod muscle	UBERON:0004252	37.67	silver quality
adult mammalian kidney	UBERON:0000082	36.85	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
kidney	UBERON:0002113	35.68	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
skeletal muscle tissue	UBERON:0001134	35.33	gold quality
muscle tissue	UBERON:0002385	34.80	gold quality
cortex of kidney	UBERON:0001225	34.37	gold quality
mucosa of transverse colon	UBERON:0004991	34.26	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	33.37	gold quality
bone marrow	UBERON:0002371	33.20	gold quality
smooth muscle tissue	UBERON:0001135	33.14	gold quality
duodenum	UBERON:0002114	33.01	silver quality
monocyte	CL:0000576	32.59	gold quality
prefrontal cortex	UBERON:0000451	32.55	silver quality
calcaneal tendon	UBERON:0003701	32.34	gold quality
zone of skin	UBERON:0000014	32.33	gold quality
skin of leg	UBERON:0001511	32.28	silver quality
fundus of stomach	UBERON:0001160	32.16	gold quality
leukocyte	CL:0000738	32.14	gold quality
skin of abdomen	UBERON:0001416	32.01	gold quality
gall bladder	UBERON:0002110	30.94	gold quality
urinary bladder	UBERON:0001255	30.40	gold quality
right adrenal gland cortex	UBERON:0035827	30.35	gold quality
metanephros cortex	UBERON:0010533	30.18	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
small intestine	UBERON:0002108	29.74	gold quality
Ammon’s horn	UBERON:0001954	29.69	gold quality
placenta	UBERON:0001987	29.21	gold quality
Brodmann (1909) area 9	UBERON:0013540	29.20	gold quality
prostate gland	UBERON:0002367	28.91	gold quality
liver	UBERON:0002107	28.89	gold quality
small intestine Peyer’s patch	UBERON:0003454	28.78	gold quality
islet of Langerhans	UBERON:0000006	27.91	gold quality
myometrium	UBERON:0001296	27.78	gold quality
intestine	UBERON:0000160	27.77	gold quality
blood	UBERON:0000178	27.65	gold quality
endometrium	UBERON:0001295	27.58	gold quality
transverse colon	UBERON:0001157	27.46	gold quality
saliva-secreting gland	UBERON:0001044	27.31	gold quality
fallopian tube	UBERON:0003889	27.19	gold quality
colon	UBERON:0001155	27.05	gold quality
superior frontal gyrus	UBERON:0002661	26.99	gold quality
subcutaneous adipose tissue	UBERON:0002190	26.93	gold quality
minor salivary gland	UBERON:0001830	26.82	gold quality
left adrenal gland cortex	UBERON:0035825	26.76	gold quality
esophagus	UBERON:0001043	26.60	gold quality
esophagus mucosa	UBERON:0002469	26.58	gold quality
right coronary artery	UBERON:0001625	26.56	gold quality
multicellular organism	UBERON:0000468	26.51	gold quality
tibial nerve	UBERON:0001323	26.44	gold quality
right adrenal gland	UBERON:0001233	26.43	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	26.30	gold quality
hypothalamus	UBERON:0001898	26.16	gold quality
lower esophagus muscularis layer	UBERON:0035833	26.09	gold quality
lower esophagus	UBERON:0013473	26.08	gold quality
putamen	UBERON:0001874	25.91	gold quality
anterior cingulate cortex	UBERON:0009835	25.82	gold quality
nucleus accumbens	UBERON:0001882	25.77	gold quality
pancreas	UBERON:0001264	25.71	gold quality
heart left ventricle	UBERON:0002084	25.55	gold quality
adrenal gland	UBERON:0002369	25.55	gold quality
gastrocnemius	UBERON:0001388	25.25	gold quality
heart	UBERON:0000948	24.84	gold quality
corpus callosum	UBERON:0002336	24.65	gold quality
tibial artery	UBERON:0007610	24.63	gold quality
primary visual cortex	UBERON:0002436	24.61	gold quality
caudate nucleus	UBERON:0001873	24.59	gold quality
popliteal artery	UBERON:0002250	24.58	gold quality
muscle layer of sigmoid colon	UBERON:0035805	24.55	gold quality
uterine cervix	UBERON:0000002	24.50	gold quality
left adrenal gland	UBERON:0001234	24.47	gold quality
adipose tissue	UBERON:0001013	24.43	gold quality
left coronary artery	UBERON:0001626	24.34	gold quality
right lobe of liver	UBERON:0001114	24.32	gold quality
left uterine tube	UBERON:0001303	24.31	gold quality
thoracic aorta	UBERON:0001515	23.84	gold quality
lung	UBERON:0002048	23.83	gold quality
ascending aorta	UBERON:0001496	23.74	gold quality
cerebellum	UBERON:0002037	23.63	gold quality
right frontal lobe	UBERON:0002810	23.57	gold quality
rectum	UBERON:0001052	23.50	gold quality
cerebellar cortex	UBERON:0002129	23.50	gold quality
body of pancreas	UBERON:0001150	23.33	gold quality
body of uterus	UBERON:0009853	23.32	gold quality
thoracic mammary gland	UBERON:0005200	23.31	gold quality
cerebellar hemisphere	UBERON:0002245	23.21	gold quality
right atrium auricular region	UBERON:0006631	22.93	gold quality
endocervix	UBERON:0000458	22.26	gold quality
right lobe of thyroid gland	UBERON:0001119	22.26	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.98

HPA expression

RNA tissue specificity: Not detected

14 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Tonsil	tissue	0.2
Skin 1	tissue	0.1
Lymph node	tissue	0.1
Cerebral cortex	tissue	0.1
Parathyroid gland	tissue	0.1
Amygdala	tissue	0.1
Superior colliculi	tissue	0.1
Kidney	tissue	0.1
Locus coeruleus	tissue	0.1
Thymus	tissue	0.1
Hippocampal formation	tissue	0.1
Olfactory bulb	tissue	0.1
Septum	tissue	0.1
Insular cortex	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 1; highest nTPM — Dorsal hippocampus (0.1).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets:

Target	Regulation
FGFR1
KRT14
KRT9

miRNA regulators (miRDB)

Targeting ASCL4 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 35 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-885-5P	99.59	68.59	879
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-7849-3P	99.47	68.17	1224
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-4263	99.18	69.25	2236
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-4751	98.80	64.95	525
HSA-MIR-513B-3P	98.76	68.12	1577
HSA-MIR-767-3P	98.61	67.69	1192
HSA-MIR-3138	98.41	67.53	744
HSA-MIR-6529-5P	97.85	66.47	673
HSA-MIR-7111-3P	97.80	66.75	1467

Functional genomics

gnomAD constraint: pLI 0.133, LOEUF 1.92, missense Z -2.78 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000342331 — one region, missense o/e 1.28.

Literature-anchored findings (GeneRIF, showing 3)

• HASH4 is involved in skin development. (PMID:15475265)
• In neuron reduced levels of ACSL4 led to a significant reduction in dendritic spine density and an alteration in spine/filopodia distribution. (PMID:19166906)
• intramitochondrial arachidonic acid and acyl-CoA synthetase 4 in angiotensin II-regulated aldosterone synthesis have roles in NCI-H295R adrenocortical cell line (PMID:22549224)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ascl4	ENSMUSG00000085111
rattus_norvegicus	Ascl4	ENSRNOG00000086355
drosophila_melanogaster	ac	FBGN0000022
drosophila_melanogaster	ase	FBGN0000137

Paralogs (4): ASCL1 (ENSG00000139352), ASCL3 (ENSG00000176009), ASCL2 (ENSG00000183734), ASCL5 (ENSG00000232237)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1914591) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 2 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased leukocyte cell number	1
absent vibrissae	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Mesocricetus auratus	Q60539	97.9%	Diamond
Oryctolagus cuniculus	P57100	96.8%	Diamond
Bos taurus	Q0VCE2	96.8%	Diamond
Ovis aries	Q28555	94.6%	Diamond
Danio rerio	Q90259	93.7%	Diamond
Xenopus laevis	Q06234	88.4%	Diamond
Gallus gallus	Q90690	86.7%	Diamond
Caenorhabditis elegans	Q10007	67.3%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PRDM4-AS1	ncRNA	101929162
PRDM4	protein-coding	11108
PWP1	protein-coding	11137
ABTB3	protein-coding	121551

Protein

Protein identifiers

Achaete-scute homolog 4 — Q6XD76 (reviewed: Q6XD76)

Alternative names: Achaete-scute-like protein 4, Class A basic helix-loop-helix protein 44

All UniProt accessions (1): Q6XD76

UniProt curated annotations — full annotation on UniProt →

Function. Could be a transcriptional regulator involved in skin development.

Subcellular location. Nucleus.

Tissue specificity. Expressed in skin. 7-fold higher expression in fetal skin than in adult skin. Weak expression also detected in fetal lung, aorta and brain, and in adult stomach, kidney, ovary and breast.

RefSeq proteins (1): NP_982260* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR050283	E-box_TF_Regulators	Family

Pfam: PF00010

UniProt features (5 total): compositionally biased region 2, chain 1, domain 1, region of interest 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6XD76-F1	71.48	0.33

Human Protein Atlas

Protein class: Predicted intracellular proteins, Transcription factors, Basic domains

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH uncertain

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 66 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, YAATNRNNNYNATT_UNKNOWN, FREAC2_01, BENPORATH_ES_WITH_H3K27ME3, RACCACAR_AML_Q6, EFC_Q6, TCF4_Q5, NKX62_Q2, AML_Q6, BRN2_01, LEF1_Q6, AML1_01, GOBP_SKIN_DEVELOPMENT, P53_DECAMER_Q2, PITX2_Q2

GO Biological Process (6): DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), skin development (GO:0043588), epithelium development (GO:0060429), negative regulation of transcription by RNA polymerase II (GO:0000122), animal organ development (GO:0048513)

GO Molecular Function (6): 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 repressor activity, RNA polymerase II-specific (GO:0001227), protein dimerization activity (GO:0046983), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), RNA polymerase II transcription regulator complex (GO:0090575), nucleus (GO:0005634), transcription regulator complex (GO:0005667)

GO top-level categories

25 GO namespaces:

Category	Terms
transcription by RNA polymerase II	2
animal gross anatomical part developmental process	2
regulation of transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
gene expression	1
RNA biosynthetic process	1
regulation of DNA-templated transcription	1
animal organ development	1
tissue development	1
negative regulation of DNA-templated transcription	1
transcription cis-regulatory region binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
protein binding	1
nucleic acid binding	1
binding	1
chromosome	1
cellular anatomical structure	1
transcription regulator complex	1
nuclear protein-containing complex	1
intracellular membrane-bounded organelle	1
protein-containing complex	1

Protein interactions and networks

STRING

showing 16 of 308 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASCL4	ACSL4	O60488	723
ASCL4	GPX4	P36969	606
ASCL4	LPCAT3	Q6P1A2	505
ASCL4	MAIP1	Q8WWC4	447
ASCL4	RMP64	Q6NW34	444
ASCL4	FTH1	P02794	427
ASCL4	SLC7A11	Q9UPY5	423
ASCL4	AIFM2	Q9BRQ8	400
ASCL4	TLCD1	Q96CP7	392
ASCL4	TMEM63C	Q9P1W3	369
ASCL4	BHLHA9	Q7RTU4	364
ASCL4	BHLHE23	Q8NDY6	358
ASCL4	TFRC	P02786	342
ASCL4	ACSL3	O95573	323
ASCL4	SLC3A2	P08195	323
ASCL4	NCOA4	Q13772	323

IntAct

Human interaction partners of ASCL4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 45 partners by confidence:

Partner	Interaction type	MIscore	Records
TCF12	physical association	0.670	6
ID2	physical association	0.670	3
HTT	physical association	0.560	6
TCF4	physical association	0.560	6
ACTA1	physical association	0.560	3
APBB2	physical association	0.560	3
ATP1A3	physical association	0.560	3
CASP6	physical association	0.560	3
CCK	physical association	0.560	3
CHAT	physical association	0.560	3
CYCS	physical association	0.560	3
DMWD	physical association	0.560	3
DNAJB6	physical association	0.560	3
DR1	physical association	0.560	3
ESR1	physical association	0.560	3
FGFR3	physical association	0.560	3
FHL3	physical association	0.560	3
FOS	physical association	0.560	3
GRB2	physical association	0.560	3
GRIA1	physical association	0.560	3
GRN	physical association	0.560	3
GTF2B	physical association	0.560	3
GTF3C3	physical association	0.560	3
HSPB1	physical association	0.560	3
KIF1B	physical association	0.560	3
LAMP2	physical association	0.560	3
MBD3	physical association	0.560	3
OPTN	physical association	0.560	3
PDZD4	physical association	0.560	3
PECAM1	physical association	0.560	3

BioGRID (21 interactions; top human partners by supporting records): TCF12 (Two-hybrid; 4 records), ID2 (Two-hybrid; 2 records), TCF4 (Two-hybrid; 2 records), ARAP3 (Affinity Capture-MS), CLIC1 (Affinity Capture-MS), CRK (Two-hybrid), DNM1 (Affinity Capture-MS), DNM2 (Affinity Capture-MS), FAM192A (Affinity Capture-MS), FHL3 (Two-hybrid), FYN (Affinity Capture-MS), ID1 (Affinity Capture-MS), MBD3 (Two-hybrid), PCYOX1 (Affinity Capture-MS), PDZD4 (Two-hybrid)

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 45 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
Constitutive Signaling by Aberrant PI3K in Cancer	5	15.9×	2e-03
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	5	12.1×	3e-03
PIP3 activates AKT signaling	6	10.0×	2e-03

Disease & clinical

Genetic variants

Variant evidence for ASCL4: 42 ClinVar records (0 pathogenic / likely pathogenic); 4 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	1
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 15 predictions of 26):

Position(s)	Effect	Δscore	Sites
12:107775469	donor_gain	0.3700
12:107775474	donor_gain	0.3400
12:107775473	donor_gain	0.3000
12:107775476	donor_gain	0.2800
12:107776550	acceptor_gain	0.2700
12:107775445	acceptor_gain	0.2500
12:107775677	donor_gain	0.2400
12:107775819	donor_gain	0.2400
12:107775817–107775819	donor_loss	0.2300	6
12:107775861	donor_gain	0.2300

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Kidney Chromophobe)

Disease associations

OMIM: gene MIM:609155 | disease phenotypes:

GWAS associations

4 associations:

Study	Trait	p-value
GCST011494_4	Daytime nap	1e-14
GCST007561_70	Sleep duration	3e-8
GCST003225_15	Pelvic organ prolapse (moderate/severe)	2e-6
GCST002481_2	Acne (severe)	5e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0007828	daytime rest measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation	1
deoxynivalenol	increases expression	1
nuciferine	decreases reaction, increases expression, increases reaction	1
arsenic disulfide	affects cotreatment, increases expression	1
isobavachalcone	increases expression, decreases reaction	1
ferrostatin-1	increases expression, decreases reaction	1
Sorafenib	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases expression	1
Dehydroepiandrosterone	decreases reaction, increases expression, increases reaction	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.