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
• 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

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.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
206882	0.0343	1

Top tissues by expression

123 total, 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

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
FGFR1
KRT14
KRT9

miRNA regulators (miRDB)

35 targeting ASCL4, 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-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

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)

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

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

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

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

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 (5): 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

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
regulation of DNA-templated transcription	1
animal organ development	1
tissue development	1
negative regulation of DNA-templated transcription	1
anatomical structure development	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

358 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASCL4	ACSL4	O60488	722
ASCL4	GPX4	P36969	519
ASCL4	MAIP1	Q8WWC4	494
ASCL4	RMP64	Q6NW34	478
ASCL4	PHF24	Q9UPV7	461
ASCL4	ARHGAP42	A6NI28	429
ASCL4	ASCL2	Q99929	410
ASCL4	GPATCH2	Q9NW75	406
ASCL4	GPATCH1	Q9BRR8	394
ASCL4	STOX2	Q9P2F5	380
ASCL4	PRSS56	P0CW18	371
ASCL4	BHLHE23	Q8NDY6	365
ASCL4	PRDM4	Q9UKN5	329
ASCL4	LPCAT3	Q6P1A2	328
ASCL4	TCF24	Q7RTU0	318

IntAct

152 interactions, top by confidence:

A	B	Type	Score
TCF12	ASCL4	psi-mi:“MI:0915”(physical association)	0.670
ASCL4	TCF12	psi-mi:“MI:0915”(physical association)	0.670
ID2	ASCL4	psi-mi:“MI:0915”(physical association)	0.670
TCF4	ASCL4	psi-mi:“MI:0915”(physical association)	0.560
ASCL4	TCF4	psi-mi:“MI:0915”(physical association)	0.560
FHL3	ASCL4	psi-mi:“MI:0915”(physical association)	0.560
ASCL4	TCF12	psi-mi:“MI:0915”(physical association)	0.560
PDZD4	ASCL4	psi-mi:“MI:0915”(physical association)	0.560
MBD3	ASCL4	psi-mi:“MI:0915”(physical association)	0.560
ASCL4	ACTA1	psi-mi:“MI:0915”(physical association)	0.560
ASCL4	APBB2	psi-mi:“MI:0915”(physical association)	0.560
ASCL4	ATP1A3	psi-mi:“MI:0915”(physical association)	0.560
CASP6	ASCL4	psi-mi:“MI:0915”(physical association)	0.560
CCK	ASCL4	psi-mi:“MI:0915”(physical association)	0.560
CHAT	ASCL4	psi-mi:“MI:0915”(physical association)	0.560
ASCL4	DMWD	psi-mi:“MI:0915”(physical association)	0.560
DR1	ASCL4	psi-mi:“MI:0915”(physical association)	0.560
ASCL4		psi-mi:“MI:0915”(physical association)	0.560
ASCL4	ESR1	psi-mi:“MI:0915”(physical association)	0.560
ASCL4	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
FOS	ASCL4	psi-mi:“MI:0915”(physical association)	0.560
	ASCL4	psi-mi:“MI:0915”(physical association)	0.560
ASCL4	GRB2	psi-mi:“MI:0915”(physical association)	0.560
GRIA1	ASCL4	psi-mi:“MI:0915”(physical association)	0.560
GRN	ASCL4	psi-mi:“MI:0915”(physical association)	0.560
GTF2B	ASCL4	psi-mi:“MI:0915”(physical association)	0.560
ASCL4	HSPB1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (20): ASCL4 (Two-hybrid), ASCL4 (Two-hybrid), ASCL4 (Two-hybrid), ASCL4 (Two-hybrid), ASCL4 (Two-hybrid), ASCL4 (Two-hybrid), ASCL4 (Two-hybrid), ASCL4 (Two-hybrid), ASCL4 (Two-hybrid), TCF4 (Two-hybrid), TCF12 (Affinity Capture-MS), DNM1 (Affinity Capture-MS), ID1 (Affinity Capture-MS), ARAP3 (Affinity Capture-MS), DNM2 (Affinity Capture-MS)

ESM2 similar proteins: A0A286YF58, A0A494C0N9, A0A494C0Y3, A0A7I2V3R4, A2VDX9, A5A769, A5PJP1, A6NIN4, A6NJG2, A6NLJ0, C9JTQ0, O14492, O15370, O35182, O43541, O88940, P0DPE3, P28283, P58267, Q12870, Q14681, Q29RM6, Q2KJ18, Q53LP3, Q60539, Q60756, Q64124, Q6F5E0, Q6QNY0, Q6XD76, Q7RTU0, Q7RTU7, Q80WY3, Q80XF7, Q86Y97, Q8BY98, Q8K025, Q8N912, Q8NCU7, Q8WY41

Diamond homologs: A8E5T6, M0QWB7, O35437, O35885, O43680, O60682, O73615, O73823, O88940, O93507, O96004, O96642, P09774, P09775, P10083, P10084, P10627, P13903, P17542, P19359, P19360, P22091, P24899, P26687, P27792, P34555, P46581, P48985, P50553, P57100, P57101, P57102, P59101, P61295, P61296, P79782, P97831, P97832, Q02067, Q02575

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 48 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	15.1×	3e-03
PIP3 activates AKT signaling	8	12.7×	8e-05
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	5	11.5×	4e-03

Disease & clinical

Clinical variants and AI predictions

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

16 predictions. Top by Δscore:

Variant	Effect	Δscore
12:107775177:G:C	acceptor_gain	0.4300
12:107775175:G:GC	acceptor_gain	0.3900
12:107775210:C:A	acceptor_gain	0.3600
12:107775173:TTGAG:T	acceptor_gain	0.3400
12:107775214:AAAT:A	acceptor_gain	0.3200
12:107775174:TGAG:T	acceptor_gain	0.3000
12:107775489:GGC:G	donor_gain	0.3000
12:107775215:A:G	acceptor_gain	0.2700
12:107774949:TTTG:T	donor_gain	0.2400
12:107775171:TATTG:T	acceptor_gain	0.2400
12:107775172:ATTGA:A	acceptor_gain	0.2400
12:107775469:G:A	donor_gain	0.2300
12:107775173:TTG:T	acceptor_gain	0.2200
12:107775359:G:GT	donor_gain	0.2200
12:107775474:C:A	donor_gain	0.2100
12:107775490:GC:G	donor_gain	0.2100

AlphaMissense

1093 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1001115278 (12:107776558 G>A,C), RS1001471635 (12:107776843 T>C), RS1003360675 (12:107773722 A>C,G), RS1004105626 (12:107776149 A>G), RS1004321633 (12:107775839 G>A), RS1006046794 (12:107776855 G>A), RS1007142603 (12:107774192 C>A,T), RS1008806498 (12:107773026 C>G), RS1008941446 (12:107773249 A>C,T), RS1010493035 (12:107772915 C>A), RS1010600621 (12:107773687 T>G), RS1011687747 (12:107774100 C>T), RS1012125840 (12:107774401 A>G), RS1013793437 (12:107775616 G>C,T), RS1014125626 (12:107776833 A>G)

Disease associations

OMIM: gene MIM:609155 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002481_2	Acne (severe)	5.000000e-06
GCST003225_2	Pelvic organ prolapse (moderate/severe)	2.000000e-06
GCST007561_70	Sleep duration	3.000000e-08
GCST011494_60	Daytime nap	1.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

10 total (human), top 10 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	decreases reaction, increases expression	1
ferrostatin-1	decreases reaction, increases expression	1
Sorafenib	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Dehydroepiandrosterone	increases reaction, decreases reaction, increases expression	1

Clinical trials (associated diseases)

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