ZSCAN4

Summary

ZSCAN4 (zinc finger and SCAN domain containing 4, HGNC:23709) is a protein-coding gene on chromosome 19q13.43, encoding Zinc finger and SCAN domain-containing protein 4 (Q8NAM6). Embryonic stem (ES) cell-specific transcription factor required to regulate ES cell pluripotency.

The ZSCAN4 gene encodes a protein involved in telomere maintenance and with a key role in the critical feature of mouse embryonic stem (ES) cells, namely, defying cellular senescence and maintaining normal karyotype for many cell divisions in culture (Zalzman et al., 2010 [PubMed 20336070]).

Source: NCBI Gene 201516 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 52 total
• MANE Select transcript: NM_152677

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23709
Approved symbol	ZSCAN4
Name	zinc finger and SCAN domain containing 4
Location	19q13.43
Locus type	gene with protein product
Status	Approved
Aliases	FLJ35105
Ensembl gene	ENSG00000180532
Ensembl biotype	protein_coding
OMIM	613419
Entrez	201516

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000318203

RefSeq mRNA: 2 — MANE Select: NM_152677 NM_001384833, NM_152677

CCDS: CCDS12958

Canonical transcript exons

ENST00000318203 — 5 exons

Exon	Start	End
ENSE00001257971	57677914	57678079
ENSE00001257982	57676041	57676541
ENSE00001498641	57668935	57669203
ENSE00001509506	57670245	57670567
ENSE00001736292	57678166	57679152

Expression profiles

Bgee: expression breadth broad, 85 present calls, max score 69.47.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2044 / max 39.4535, expressed in 75 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177789	0.0883	35
177790	0.0723	26
177788	0.0324	8
208949	0.0114	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelium of nasopharynx	UBERON:0001951	69.47	gold quality
mucosa of paranasal sinus	UBERON:0005030	64.64	gold quality
placenta	UBERON:0001987	64.13	gold quality
apex of heart	UBERON:0002098	62.96	gold quality
superficial temporal artery	UBERON:0001614	62.89	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	61.02	gold quality
mammary duct	UBERON:0001765	58.30	gold quality
right uterine tube	UBERON:0001302	58.07	gold quality
lower lobe of lung	UBERON:0008949	57.40	silver quality
vena cava	UBERON:0004087	56.53	gold quality
germinal epithelium of ovary	UBERON:0001304	55.84	gold quality
amniotic fluid	UBERON:0000173	55.60	gold quality
skin of abdomen	UBERON:0001416	54.34	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	53.71	gold quality
gingival epithelium	UBERON:0001949	53.57	gold quality
mammalian vulva	UBERON:0000997	53.15	gold quality
biceps brachii	UBERON:0001507	52.58	gold quality
vastus lateralis	UBERON:0001379	51.43	gold quality
quadriceps femoris	UBERON:0001377	51.18	gold quality
nasal cavity mucosa	UBERON:0001826	50.46	gold quality
zone of skin	UBERON:0000014	50.27	gold quality
gingiva	UBERON:0001828	49.58	gold quality
urinary bladder	UBERON:0001255	49.55	gold quality
skin of leg	UBERON:0001511	49.39	gold quality
minor salivary gland	UBERON:0001830	49.15	gold quality
pigmented layer of retina	UBERON:0001782	48.84	gold quality
mouth mucosa	UBERON:0003729	48.80	gold quality
saliva-secreting gland	UBERON:0001044	47.92	gold quality
skin of hip	UBERON:0001554	47.43	gold quality
body of stomach	UBERON:0001161	46.41	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	2660.96
E-ANND-3	no	3.76

Regulation

Is transcription factor: yes

JASPAR motifs

Motif	Name	Family
MA1155.1	ZSCAN4	More than 3 adjacent zinc fingers

JASPAR matrix evidence (PMIDs): PMID:28092692

Upstream regulators (CollecTRI, top): RIF1

miRNA regulators (miRDB)

18 targeting ZSCAN4, 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-4789-5P	99.98	70.76	2721
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-888-3P	99.53	69.77	1057
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-3606-5P	99.31	69.67	1168
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-4272	98.76	68.74	1810
HSA-MIR-5581-3P	98.55	70.31	1161
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-625-3P	97.32	66.55	554
HSA-MIR-3935	96.33	66.79	797

Literature-anchored findings (GeneRIF, showing 10)

• The direct interaction between Zscan4 and Rap1 may explain how Zscan4 rapidly increases telomere length, yielding important information about the role of these proteins in telomere biology. (PMID:24840609)
• ZSCAN4 indirectly interacts with TRF1 in cancer cells. We show that ZSCAN4 plays an important role independent of telomere maintenance pathways (telomerase positive and alternative pathway) or cell lineage. (PMID:26403970)
• the expression and function of each gene copy of Zscan4 locus in a physiological context, is reported. (PMID:27699651)
• Zscan4 may play critical roles during late meiotic prophase in both males and females. (PMID:27699653)
• RNF20 depletion stabilizes the ZSCAN4 protein half-life, suggesting that RNF20 negatively regulates ZSCAN4 stability. (PMID:29477841)
• The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1. (PMID:29712904)
• ZSCAN4 facilitates chromatin remodeling and promotes the cancer stem cell phenotype. (PMID:32507861)
• The Zscan4-Tet2 Transcription Nexus Regulates Metabolic Rewiring and Enhances Proteostasis to Promote Reprogramming. (PMID:32668244)
• Low expression of ZSCAN4 predicts unfavorable outcome in urothelial carcinoma of upper urinary tract and urinary bladder. (PMID:36841776)
• ZSCAN4-binding motif-TGCACAC is conserved and enriched in CA/TG microsatellites in both mouse and human genomes. (PMID:38153767)

Cross-species orthologs

0 orthologs

Paralogs (30): ZNF263 (ENSG00000006194), ZNF213 (ENSG00000085644), ZNF500 (ENSG00000103199), ZKSCAN1 (ENSG00000106261), ZNF205 (ENSG00000122386), ZSCAN9 (ENSG00000137185), PGBD1 (ENSG00000137338), ZNF215 (ENSG00000149054), ZSCAN12 (ENSG00000158691), ZNF394 (ENSG00000160908), ZNF75A (ENSG00000162086), ZSCAN21 (ENSG00000166529), ZNF232 (ENSG00000167840), ZNF24 (ENSG00000172466), ZNF449 (ENSG00000173275), ZSCAN22 (ENSG00000182318), ZNF75D (ENSG00000186376), ZNF396 (ENSG00000186496), ZNF397 (ENSG00000186812), ZSCAN30 (ENSG00000186814), ZKSCAN4 (ENSG00000187626), ZSCAN23 (ENSG00000187987), ZKSCAN3 (ENSG00000189298), ZSCAN16 (ENSG00000196812), ZSCAN25 (ENSG00000197037), ZSCAN26 (ENSG00000197062), ZNF165 (ENSG00000197279), ZKSCAN8 (ENSG00000198315), ZSCAN31 (ENSG00000235109), ZNF853 (ENSG00000236609)

Protein

Protein identifiers

Zinc finger and SCAN domain-containing protein 4 — Q8NAM6 (reviewed: Q8NAM6)

Alternative names: Zinc finger protein 494

All UniProt accessions (1): Q8NAM6

UniProt curated annotations — full annotation on UniProt →

Function. Embryonic stem (ES) cell-specific transcription factor required to regulate ES cell pluripotency. Binds telomeres and plays a key role in genomic stability in ES cells by regulating telomere elongation. Acts as an activator of spontaneous telomere sister chromatid exchange (T-SCE) and telomere elongation in undifferentiated ES cells.

Subcellular location. Nucleus. Chromosome. Telomere.

RefSeq proteins (2): NP_001371762, NP_689890* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003309	SCAN_dom	Domain
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR038269	SCAN_sf	Homologous_superfamily

Pfam: PF00096, PF02023

UniProt features (12 total): zinc finger region 4, compositionally biased region 3, region of interest 2, chain 1, domain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NAM6-F1	51.09	0.08

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9819196	Zygotic genome activation (ZGA)

MSigDB gene sets: 36 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_NEGATIVE_REGULATION_OF_DNA_RECOMBINATION, GOBP_TELOMERE_MAINTENANCE_VIA_TELOMERE_LENGTHENING, GOBP_TELOMERE_ORGANIZATION, GOBP_MITOTIC_RECOMBINATION, GOCC_CHROMOSOMAL_REGION, GOCC_CHROMOSOME_TELOMERIC_REGION, GOBP_DNA_METABOLIC_PROCESS, GOBP_DNA_RECOMBINATION, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, GOBP_NEGATIVE_REGULATION_OF_DNA_METABOLIC_PROCESS, GOBP_REGULATION_OF_MITOTIC_RECOMBINATION, GOBP_NEGATIVE_REGULATION_OF_NUCLEOBASE_CONTAINING_COMPOUND_METABOLIC_PROCESS, MADAN_DPPA4_TARGETS

GO Biological Process (3): regulation of transcription by RNA polymerase II (GO:0006357), telomere maintenance via telomere lengthening (GO:0010833), negative regulation of mitotic recombination (GO:0045950)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), zinc ion binding (GO:0008270), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (3): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Maternal to zygotic transition (MZT)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
telomere maintenance	1
regulation of mitotic recombination	1
mitotic recombination	1
negative regulation of DNA recombination	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
transition metal ion binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
DNA binding	1
cation binding	1
chromosomal region	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

712 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZSCAN4	TRIM43	Q96BQ3	773
ZSCAN4	DUX4L2	P0CJ85	768
ZSCAN4	MBD3L2	Q8NHZ7	762
ZSCAN4	LEUTX	A8MZ59	667
ZSCAN4	PRAMEF1	O95521	660
ZSCAN4	UBTFL1	P0CB47	624
ZSCAN4	DPPA2	Q7Z7J5	623
ZSCAN4	SMCHD1	A6NHR9	587
ZSCAN4	TMEM92	Q6UXU6	586
ZSCAN4	KHDC1L	Q5JSQ8	581
ZSCAN4	DUXA	A6NLW8	579
ZSCAN4	KHDC1	Q4VXA5	578
ZSCAN4	DPPA4	Q7L190	571
ZSCAN4	NANOG	Q9H9S0	524
ZSCAN4	RFPL2	O75678	522

IntAct

41 interactions, top by confidence:

A	B	Type	Score
KAT5	ZSCAN4	psi-mi:“MI:0915”(physical association)	0.560
CIB3	ZSCAN4	psi-mi:“MI:0915”(physical association)	0.560
CTBP2	ZSCAN4	psi-mi:“MI:0915”(physical association)	0.560
PARD6B	ZSCAN4	psi-mi:“MI:0915”(physical association)	0.560
ZSCAN4	EXOC8	psi-mi:“MI:0915”(physical association)	0.560
HCK	ZSCAN4	psi-mi:“MI:0915”(physical association)	0.560
TBC1D22B	ZSCAN4	psi-mi:“MI:0915”(physical association)	0.560
FAM110A	ZSCAN4	psi-mi:“MI:0915”(physical association)	0.560
TRAF3	ZSCAN4	psi-mi:“MI:0915”(physical association)	0.560
ZSCAN4	LAMTOR3	psi-mi:“MI:0915”(physical association)	0.560
ZSCAN4	KAT5	psi-mi:“MI:0915”(physical association)	0.560
HAT1	ZSCAN4	psi-mi:“MI:0915”(physical association)	0.560
ZSCAN4	CIB3	psi-mi:“MI:0915”(physical association)	0.560
ZSCAN4	PARD6B	psi-mi:“MI:0915”(physical association)	0.560
ZSCAN4	TBC1D22B	psi-mi:“MI:0915”(physical association)	0.560
EXOC8	ZSCAN4	psi-mi:“MI:0915”(physical association)	0.560
ZSCAN4	FAM110A	psi-mi:“MI:0915”(physical association)	0.560
	ZSCAN4	psi-mi:“MI:0915”(physical association)	0.370
TNF	ZSCAN4	psi-mi:“MI:0915”(physical association)	0.370
TNFSF14	ZSCAN4	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (17): RNF20 (Affinity Capture-Western), RNF20 (Co-localization), ZSCAN4 (Two-hybrid), ZSCAN4 (Two-hybrid), ZSCAN4 (Two-hybrid), ZSCAN4 (Two-hybrid), ZSCAN4 (Two-hybrid), ZSCAN4 (Two-hybrid), ZSCAN4 (Two-hybrid), ZSCAN4 (Two-hybrid), ZSCAN4 (Two-hybrid), ZSCAN4 (Two-hybrid), ZSCAN4 (Two-hybrid), ZNF217 (Affinity Capture-MS), ZSCAN4 (Two-hybrid)

ESM2 similar proteins: A0A1B0GTS1, A0A1B0GWH4, A1A4L6, A1YGI6, A6NDR6, B8QB46, F1MJR8, F1QDF8, O35892, O35893, P09015, P15036, P15037, P23497, P52729, P59598, Q32NH9, Q3KRF1, Q3UM89, Q4G112, Q4V7E1, Q5M7N6, Q5ND04, Q5XIV2, Q5ZHX5, Q66IG8, Q6P1R3, Q6PCX9, Q6PJQ5, Q708W2, Q76I76, Q76I79, Q76N89, Q7M6U3, Q8AXQ4, Q8BVK9, Q8IUE0, Q8IUE1, Q8IWB6, Q8IXJ9

Diamond homologs: A1YEP8, A1YFW2, A1YFX5, A1YG60, A1YGJ4, A2T6E3, A2T6V8, A2T736, A2T7D7, A2T7F4, A2T7G6, A6QNZ0, A7KBS4, D2HQI1, O14978, O15535, O43309, O60304, P0CG00, P10073, P17028, P49910, Q15697, Q15776, Q16670, Q1LZ87, Q3MJ62, Q3URS2, Q4R8H9, Q5RAE6, Q5RJ54, Q5SXI5, Q6NSZ9, Q6R2W3, Q80VJ6, Q86W11, Q8BGS3, Q8CF60, Q8IWY8, Q8N0Y2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	44
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

557 predictions. Top by Δscore:

Variant	Effect	Δscore
19:57676039:A:AG	acceptor_gain	1.0000
19:57676040:G:GC	acceptor_loss	1.0000
19:57676040:G:GG	acceptor_gain	1.0000
19:57676538:CTTA:C	donor_gain	1.0000
19:57676539:TTA:T	donor_gain	1.0000
19:57676540:TA:T	donor_gain	1.0000
19:57676540:TAGT:T	donor_loss	1.0000
19:57676541:AG:A	donor_loss	1.0000
19:57676542:G:GG	donor_gain	1.0000
19:57677909:TACA:T	acceptor_loss	1.0000
19:57677912:A:AC	acceptor_loss	1.0000
19:57677912:A:AG	acceptor_gain	1.0000
19:57677913:G:GG	acceptor_gain	1.0000
19:57678164:A:AG	acceptor_gain	1.0000
19:57678165:G:GG	acceptor_gain	1.0000
19:57676040:GC:G	acceptor_gain	0.9900
19:57676040:GCTT:G	acceptor_gain	0.9900
19:57676537:CCTTA:C	donor_gain	0.9900
19:57676543:TG:T	donor_loss	0.9900
19:57676544:GAGT:G	donor_loss	0.9900
19:57676545:AGTA:A	donor_loss	0.9900
19:57677913:GGT:G	acceptor_gain	0.9900
19:57677913:GGTC:G	acceptor_gain	0.9900
19:57677913:GGTCC:G	acceptor_gain	0.9900
19:57678078:AGGTA:A	donor_loss	0.9900
19:57678080:G:A	donor_loss	0.9900
19:57678081:T:G	donor_loss	0.9900
19:57678160:TCACA:T	acceptor_loss	0.9900
19:57678161:CACAG:C	acceptor_loss	0.9900
19:57678163:C:CG	acceptor_loss	0.9900

AlphaMissense

2873 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:57678732:T:C	F377L	1.000
19:57678734:C:A	F377L	1.000
19:57678734:C:G	F377L	1.000
19:57678795:T:C	C398R	1.000
19:57678564:T:C	F321L	0.999
19:57678566:T:A	F321L	0.999
19:57678566:T:G	F321L	0.999
19:57678627:T:C	C342R	0.999
19:57678648:T:C	F349L	0.999
19:57678650:C:A	F349L	0.999
19:57678650:C:G	F349L	0.999
19:57678667:T:C	L355P	0.999
19:57678711:T:C	C370R	0.999
19:57678713:C:G	C370W	0.999
19:57678720:T:C	C373R	0.999
19:57678733:T:C	F377S	0.999
19:57678797:T:G	C398W	0.999
19:57678804:T:C	C401R	0.999
19:57678806:T:G	C401W	0.999
19:57678816:T:G	Y405D	0.999
19:57678834:T:G	Y411D	0.999
19:57678841:G:C	R413P	0.999
19:57678552:T:C	C317R	0.998
19:57678675:C:G	H358D	0.998
19:57678679:A:C	Q359P	0.998
19:57678705:T:C	F368L	0.998
19:57678707:C:A	F368L	0.998
19:57678707:C:G	F368L	0.998
19:57678720:T:A	C373S	0.998
19:57678721:G:C	C373S	0.998

dbSNP variants (sampled 300 via entrez): RS1000170822 (19:57664202 A>C), RS1000342500 (19:57657954 G>T), RS1000360902 (19:57679160 G>A,C), RS1000576195 (19:57667913 T>C), RS1000587331 (19:57650612 A>G), RS1000595984 (19:57673586 G>A), RS1000627028 (19:57657563 G>A), RS1000809665 (19:57664203 G>A), RS1000928419 (19:57664437 G>T), RS1001013263 (19:57662151 T>C), RS1001246855 (19:57656457 C>A,T), RS1001292116 (19:57655126 C>T), RS1001326834 (19:57676888 C>T), RS1001369358 (19:57667955 G>T), RS1001381334 (19:57670075 G>A)

Disease associations

OMIM: gene MIM:613419 | 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)

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	5
Aflatoxin B1	affects expression, increases expression, increases methylation	4
TAK-243	increases sumoylation	1
ethyl-p-hydroxybenzoate	increases expression	1
CGP 52608	affects binding, increases reaction	1
Decitabine	increases expression	1
Acetaminophen	increases expression	1
Cadmium	decreases expression, increases abundance	1
Endosulfan	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Fenfluramine	increases expression	1
Formaldehyde	increases expression	1
Methyl Methanesulfonate	increases expression	1
Naled	affects expression	1
Quercetin	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Okadaic Acid	increases expression	1

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8K9	SEES3-1V human ZSCAN4, clone1	Embryonic stem cell	Male
CVCL_A8L0	SEES3-1V human ZSCAN4, clone2	Embryonic stem cell	Male
CVCL_A8L1	SEES3-1V human ZSCAN4, clone3	Embryonic stem cell	Male
CVCL_HD49	HEK293 eGFP-ZSCAN4	Transformed cell line	Female

Clinical trials (associated diseases)

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