EID3

Summary

EID3 (EP300 interacting inhibitor of differentiation 3, HGNC:32961) is a protein-coding gene on chromosome 12q23.3, encoding EP300-interacting inhibitor of differentiation 3 (Q8N140). Tissue-specific component of the SMC5-SMC6 complex, a complex involved in repair of DNA double-strand breaks by homologous recombination.

Predicted to be involved in DNA repair. Located in nucleolus and nucleoplasm. Part of Smc5-Smc6 complex.

Source: NCBI Gene 493861 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 57 total
• MANE Select transcript: NM_001008394

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:32961
Approved symbol	EID3
Name	EP300 interacting inhibitor of differentiation 3
Location	12q23.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ25832, NSMCE4B, NSE4B
Ensembl gene	ENSG00000255150
Ensembl biotype	protein_coding
OMIM	612986
Entrez	493861

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000527879

RefSeq mRNA: 1 — MANE Select: NM_001008394 NM_001008394

CCDS: CCDS53822

Canonical transcript exons

ENST00000527879 — 1 exons

Exon	Start	End
ENSE00002159830	104303739	104305205

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 94.59.

FANTOM5 (CAGE): breadth broad, TPM avg 2.0445 / max 206.1458, expressed in 666 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
127738	2.0109	661
127737	0.0199	4
127736	0.0137	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	94.59	gold quality
right testis	UBERON:0004534	94.49	gold quality
testis	UBERON:0000473	93.30	gold quality
sperm	CL:0000019	93.14	gold quality
secondary oocyte	CL:0000655	88.12	gold quality
oocyte	CL:0000023	88.01	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.53	gold quality
adult organism	UBERON:0007023	87.46	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.48	gold quality
epithelial cell of pancreas	CL:0000083	79.05	silver quality
calcaneal tendon	UBERON:0003701	78.71	gold quality
granulocyte	CL:0000094	77.61	gold quality
adrenal tissue	UBERON:0018303	75.90	gold quality
lymph node	UBERON:0000029	72.63	gold quality
oviduct epithelium	UBERON:0004804	72.62	gold quality
lower esophagus muscularis layer	UBERON:0035833	72.55	gold quality
lower esophagus	UBERON:0013473	72.50	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	72.38	gold quality
mucosa of stomach	UBERON:0001199	72.35	gold quality
germinal epithelium of ovary	UBERON:0001304	72.27	gold quality
vermiform appendix	UBERON:0001154	71.37	gold quality
ovary	UBERON:0000992	70.97	gold quality
islet of Langerhans	UBERON:0000006	70.79	gold quality
descending thoracic aorta	UBERON:0002345	70.64	gold quality
bone marrow cell	CL:0002092	70.61	silver quality
prefrontal cortex	UBERON:0000451	70.61	gold quality
endothelial cell	CL:0000115	70.46	silver quality
smooth muscle tissue	UBERON:0001135	70.42	gold quality
left uterine tube	UBERON:0001303	70.24	gold quality
left coronary artery	UBERON:0001626	70.24	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.63
E-MTAB-7249	no	116.68

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KMT5B

miRNA regulators (miRDB)

8 targeting EID3, 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-218-5P	99.93	72.22	2103
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-10524-5P	99.05	66.08	963
HSA-MIR-654-3P	98.38	67.61	905
HSA-MIR-633	98.35	69.45	1167
HSA-MIR-424-3P	97.20	65.86	385
HSA-MIR-4761-3P	96.27	66.26	524

Literature-anchored findings (GeneRIF, showing 5)

• EID3 acts as an inhibitor of CBP/p300-dependent transcription in a tissue-specific manner. (PMID:15987788)
• These findings indicated a novel mechanism by which EID3, a p300 acetyltransferase inhibitor, could directly affect DNMT3A, this enzyme possesses dual methylation and demethylation abilities. (PMID:28074931)
• Knockdown of EID3 by specific shRNA attenuated BMS-345541 -induced radiosensitization in MCF-7 cells. (PMID:30114644)
• EID3 Promotes Cancer Stem Cell-Like Phenotypes in Osteosarcoma through the Activation of PI3K-AKT Signaling Pathway. (PMID:36071872)
• EID3 inhibits the osteogenic differentiation of periodontal ligament stem cells and mediates the signal transduction of TAZ-EID3-AKT/MTOR/ERK. (PMID:38216090)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nsmce4a	ENSDARG00000024311
mus_musculus	Eid3	ENSMUSG00000109864
rattus_norvegicus	Eid3	ENSRNOG00000075657
drosophila_melanogaster	Nse4	FBGN0032251
caenorhabditis_elegans		WBGENE00010409

Paralogs (1): NSMCE4A (ENSG00000107672)

Protein

Protein identifiers

EP300-interacting inhibitor of differentiation 3 — Q8N140 (reviewed: Q8N140)

Alternative names: E1A-like inhibitor of differentiation 3, EID-1-like inhibitor of differentiation 3, Non-structural maintenance of chromosomes element 4 homolog B

All UniProt accessions (2): A0A140VJI9, Q8N140

UniProt curated annotations — full annotation on UniProt →

Function. Tissue-specific component of the SMC5-SMC6 complex, a complex involved in repair of DNA double-strand breaks by homologous recombination. The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination and mediates sumoylation of shelterin complex (telosome) components. Acts as a repressor of nuclear receptor-dependent transcription possibly by interfering with CREBBP-dependent coactivation. May function as a coinhibitor of other CREBBP/EP300-dependent transcription factors.

Subunit / interactions. Component of the SMC5-SMC6 complex which consists at least of SMC5, SMC6, NSMCE2, NSMCE1, NSMCE4A or EID3 and NSMCE3; EID3 seems to be a testis-specific subunit. NSMCE1, NSMCE4A or EID3 and NSMCE3 probably form a subcomplex that bridges the head domains of the SMC5:SMC6 heterodimer. Homodimer, and heterodimer with EID2. Interacts with the C-terminal region of CREBBP.

Subcellular location. Nucleus. Cytoplasm. Chromosome. Telomere.

Tissue specificity. Highly expressed in testis.

Similarity. Belongs to the NSE4 family.

RefSeq proteins (1): NP_001008395* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR014854	Nse4_C	Domain
IPR027786	Nse4/EID	Family
IPR029225	Nse4_Nse3-bd	Domain

Pfam: PF08743, PF15412

UniProt features (1 total): chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9LWI	ELECTRON MICROSCOPY	3.12
9LWJ	ELECTRON MICROSCOPY	7.19
9LWL	ELECTRON MICROSCOPY	7.25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N140-F1	73.67	0.21

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins

MSigDB gene sets: 71 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_TELOMERE_ORGANIZATION, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_UP, GOBP_REGULATION_OF_TELOMERE_MAINTENANCE, GOBP_PEPTIDYL_LYSINE_MODIFICATION, GOBP_PROTEIN_SUMOYLATION, GOBP_DNA_DAMAGE_RESPONSE, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_REGULATION_OF_CHROMOSOME_ORGANIZATION, GOBP_RECOMBINATIONAL_REPAIR, MELLMAN_TUT1_TARGETS_DN, GOCC_CHROMOSOMAL_REGION, GOCC_TRANSFERASE_COMPLEX, GOCC_CHROMOSOME_TELOMERIC_REGION, GOCC_NUCLEOLUS

GO Biological Process (7): double-strand break repair via homologous recombination (GO:0000724), DNA repair (GO:0006281), protein sumoylation (GO:0016925), regulation of telomere maintenance (GO:0032204), chromatin looping (GO:0140588), DNA recombination (GO:0006310), DNA damage response (GO:0006974)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (7): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), Smc5-Smc6 complex (GO:0030915), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	2
nuclear lumen	2
cellular anatomical structure	2
intracellular membraneless organelle	2
recombinational repair	1
double-strand break repair	1
DNA damage response	1
peptidyl-lysine modification	1
protein modification by small protein conjugation	1
telomere maintenance	1
regulation of chromosome organization	1
regulation of DNA metabolic process	1
chromatin organization	1
cellular response to stress	1
binding	1
chromosomal region	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
condensed chromosome	1
SUMO ligase complex	1

Protein interactions and networks

STRING

392 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EID3	SMC5	Q8IY18	910
EID3	EID2	Q8N6I1	890
EID3	EID1	Q9Y6B2	855
EID3	SMC6	Q96SB8	798
EID3	TXNRD1	Q16881	687
EID3	NSMCE3	Q96MG7	630
EID3	CREBBP	Q92793	613
EID3	RAD17	O75943	564
EID3	EID2B	Q96D98	542
EID3	EP300	Q09472	483
EID3	MAGEF1	Q9HAY2	483
EID3	NR5A1	Q13285	479
EID3	NSMCE2	Q96MF7	471
EID3	DNMT3A	Q9Y6K1	458
EID3	DNMT1	P26358	398

IntAct

20 interactions, top by confidence:

A	B	Type	Score
EID3	NSMCE1	psi-mi:“MI:0915”(physical association)	0.830
EID3	NSMCE1	psi-mi:“MI:0914”(association)	0.830
NSMCE3	EID3	psi-mi:“MI:0915”(physical association)	0.820
EID3	NSMCE3	psi-mi:“MI:0915”(physical association)	0.820
NSMCE3	EID3	psi-mi:“MI:0914”(association)	0.820
EID3	SMC5	psi-mi:“MI:0915”(physical association)	0.740
MAGEA1	EID3	psi-mi:“MI:0914”(association)	0.500
EID3	MAGEA1	psi-mi:“MI:0914”(association)	0.500
EID3	MAGEA1	psi-mi:“MI:0915”(physical association)	0.500
MAGED4B	EID3	psi-mi:“MI:0915”(physical association)	0.400
EID3	NDN	psi-mi:“MI:0915”(physical association)	0.400
EID2B	EID3	psi-mi:“MI:0915”(physical association)	0.400
APPBP2	EID3	psi-mi:“MI:0915”(physical association)	0.370
EID3	ACSL4	psi-mi:“MI:0914”(association)	0.350
EID3	NAB2	psi-mi:“MI:0914”(association)	0.350

BioGRID (70): EID3 (Affinity Capture-Western), EID3 (Reconstituted Complex), NMT1 (Affinity Capture-MS), TLK2 (Affinity Capture-MS), SMC6 (Affinity Capture-MS), AKAP12 (Affinity Capture-MS), ACSL4 (Affinity Capture-MS), NSMCE2 (Affinity Capture-MS), SLC27A2 (Affinity Capture-MS), NDNL2 (Affinity Capture-MS), SMC5 (Affinity Capture-MS), NCAPH (Affinity Capture-MS), NSMCE1 (Affinity Capture-MS), PTGES2 (Affinity Capture-MS), APOL2 (Affinity Capture-MS)

ESM2 similar proteins: A2AU37, A5LFW4, A6QPC8, A9SV60, A9SY64, B0BN28, C0SV12, C6KIE6, F4HZD1, F4JET1, F4K3G5, F4K487, K7TQE3, O65312, O82504, Q0V7M7, Q10SU5, Q13156, Q2RBJ4, Q2TBI1, Q3V124, Q4V3E2, Q4V8G2, Q56Y74, Q5RH01, Q6AUQ7, Q6S5G3, Q75PQ8, Q8H1E8, Q8N140, Q94HV8, Q9C5P0, Q9C5P1, Q9C689, Q9C6G0, Q9CPV1, Q9FJX9, Q9FKV5, Q9FT92, Q9LFQ9

Diamond homologs: A5LFW4, A6QPC8, P43124, Q2TBI1, Q3V124, Q4V8G2, Q8N140, Q9NXX6

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
KMT5B	“up-regulates quantity by expression”	EID3	“transcriptional regulation”
EID3	down-regulates	Skeletal_muscle_differentiation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

185 predictions. Top by Δscore:

Variant	Effect	Δscore
12:104303780:ACGCT:A	acceptor_gain	0.9800
12:104303783:CTGGG:C	acceptor_gain	0.9800
12:104303784:T:A	acceptor_gain	0.9800
12:104303781:C:G	acceptor_gain	0.9700
12:104304450:T:TA	acceptor_gain	0.9700
12:104303784:TGGG:T	acceptor_gain	0.9600
12:104303785:G:A	acceptor_gain	0.9600
12:104303780:AC:A	acceptor_gain	0.9500
12:104303781:C:CA	acceptor_gain	0.9500
12:104304596:TAGA:T	donor_gain	0.9500
12:104304597:AGAA:A	donor_gain	0.9500
12:104303780:A:AG	acceptor_gain	0.9200
12:104303787:G:C	acceptor_gain	0.9200
12:104304633:A:T	donor_gain	0.9200
12:104304315:G:A	acceptor_gain	0.8800
12:104304245:C:T	donor_gain	0.8700
12:104304559:GACC:G	donor_gain	0.8500
12:104304461:A:G	acceptor_gain	0.8300
12:104304460:A:AG	acceptor_gain	0.8200
12:104304148:G:GT	donor_gain	0.8100
12:104304187:G:GT	donor_gain	0.7600
12:104304314:T:TA	acceptor_gain	0.7500
12:104303779:C:G	acceptor_gain	0.7300
12:104304594:C:G	donor_gain	0.7300
12:104304462:GCTA:G	acceptor_gain	0.7200
12:104304263:A:G	donor_gain	0.6900
12:104303778:ACAC:A	acceptor_gain	0.6800
12:104304603:G:GT	donor_gain	0.6800
12:104304462:G:GG	acceptor_gain	0.6700
12:104304636:G:GG	donor_gain	0.6700

AlphaMissense

2229 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:104304874:T:A	W314R	0.996
12:104304874:T:C	W314R	0.996
12:104304685:T:C	S251P	0.995
12:104304151:G:C	A73P	0.994
12:104304202:G:C	A90P	0.994
12:104304671:T:A	V246E	0.993
12:104304688:T:C	F252L	0.993
12:104304690:T:A	F252L	0.993
12:104304690:T:G	F252L	0.993
12:104304190:G:C	A86P	0.992
12:104304698:C:T	T255I	0.992
12:104304724:T:C	F264L	0.992
12:104304726:T:A	F264L	0.992
12:104304726:T:G	F264L	0.992
12:104304617:T:C	L228S	0.991
12:104304220:G:C	A96P	0.990
12:104304746:C:A	A271E	0.989
12:104304068:G:C	R45P	0.988
12:104304689:T:C	F252S	0.988
12:104304658:T:G	Y242D	0.987
12:104304697:A:C	T255P	0.987
12:104304782:T:C	L283S	0.987
12:104304875:G:C	W314S	0.986
12:104304776:C:G	P281R	0.985
12:104304212:T:C	L93P	0.984
12:104304776:C:A	P281Q	0.984
12:104304668:T:C	F245S	0.983
12:104304719:T:A	V262D	0.983
12:104304876:G:C	W314C	0.983
12:104304876:G:T	W314C	0.983

dbSNP variants (sampled 300 via entrez): RS1000106768 (12:104303449 T>G), RS1000293297 (12:104302742 G>T), RS1002688695 (12:104303026 CT>C), RS1003058269 (12:104301911 T>G), RS1003631224 (12:104305228 C>T), RS1004535145 (12:104303921 C>A,T), RS1005205956 (12:104303759 C>A,G,T), RS1006035174 (12:104305472 T>G), RS1007091655 (12:104303701 C>T), RS1007427339 (12:104302254 T>C), RS1007468811 (12:104303847 G>A,T), RS1008532695 (12:104303212 G>T), RS1008647213 (12:104303515 T>A), RS1009561091 (12:104302593 C>T), RS1009581348 (12:104303427 A>C)

Disease associations

OMIM: gene MIM:612986 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002549_8	Response to serotonin reuptake inhibitors in major depressive disorder (plasma drug and metabolite levels)	7.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005658	response to selective serotonin reuptake inhibitor

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

51 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	6
sodium arsenite	increases expression, increases stability	2
mercuric bromide	decreases expression, affects cotreatment	2
Air Pollutants	increases abundance, increases expression	2
Tobacco Smoke Pollution	increases expression	2
Cadmium Chloride	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
bisphenol A	affects cotreatment, decreases expression	1
trichostatin A	decreases expression	1
2-butenal	increases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
ferrous chloride	increases expression	1
hydroquinone	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	decreases expression	1
quinocetone	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Allergens	decreases expression	1
Azathioprine	increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Drugs, Chinese Herbal	increases expression	1
Estradiol	increases expression	1

Clinical trials (associated diseases)

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