EGR4

Summary

EGR4 (early growth response 4, HGNC:3241) is a protein-coding gene on chromosome 2p13.2, encoding Early growth response protein 4 (Q05215). Transcriptional regulator.

Enables DNA-binding transcription activator activity, RNA polymerase II-specific and sequence-specific double-stranded DNA binding activity. Involved in positive regulation of transcription by RNA polymerase II. Predicted to be located in chromatin.

Source: NCBI Gene 1961 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 129 total
• Transcription factor: yes — 15 downstream targets (CollecTRI)
• MANE Select transcript: NM_001965

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3241
Approved symbol	EGR4
Name	early growth response 4
Location	2p13.2
Locus type	gene with protein product
Status	Approved
Aliases	NGFI-C, PAT133
Ensembl gene	ENSG00000135625
Ensembl biotype	protein_coding
OMIM	128992
Entrez	1961

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000436467, ENST00000545030, ENST00000858695

RefSeq mRNA: 1 — MANE Select: NM_001965 NM_001965

CCDS: CCDS1925

Canonical transcript exons

ENST00000436467 — 2 exons

Exon	Start	End
ENSE00001605350	73290929	73292781
ENSE00002040609	73293182	73293548

Expression profiles

Bgee: expression breadth ubiquitous, 104 present calls, max score 95.14.

FANTOM5 (CAGE): breadth broad, TPM avg 4.8950 / max 527.3692, expressed in 342 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
29138	4.8950	342

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory bulb	UBERON:0002264	95.14	silver quality
type B pancreatic cell	CL:0000169	94.83	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.87	gold quality
CA1 field of hippocampus	UBERON:0003881	82.44	gold quality
endothelial cell	CL:0000115	82.11	gold quality
triceps brachii	UBERON:0001509	79.78	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.25	gold quality
diaphragm	UBERON:0001103	79.07	gold quality
pancreatic ductal cell	CL:0002079	78.53	silver quality
putamen	UBERON:0001874	78.31	gold quality
gluteal muscle	UBERON:0002000	78.11	gold quality
Brodmann (1909) area 46	UBERON:0006483	77.84	gold quality
nucleus accumbens	UBERON:0001882	77.06	gold quality
entorhinal cortex	UBERON:0002728	77.00	gold quality
orbitofrontal cortex	UBERON:0004167	76.88	gold quality
middle temporal gyrus	UBERON:0002771	76.55	gold quality
right hemisphere of cerebellum	UBERON:0014890	76.32	gold quality
parietal lobe	UBERON:0001872	76.20	gold quality
primary visual cortex	UBERON:0002436	75.84	gold quality
postcentral gyrus	UBERON:0002581	75.84	gold quality
cerebellum	UBERON:0002037	75.59	gold quality
caudate nucleus	UBERON:0001873	75.42	gold quality
cerebellar cortex	UBERON:0002129	75.38	gold quality
occipital lobe	UBERON:0002021	75.37	gold quality
cerebellar hemisphere	UBERON:0002245	75.21	gold quality
superior frontal gyrus	UBERON:0002661	74.84	gold quality
prefrontal cortex	UBERON:0000451	74.31	gold quality
lateral globus pallidus	UBERON:0002476	74.05	gold quality
hair follicle	UBERON:0002073	73.94	gold quality
Brodmann (1909) area 23	UBERON:0013554	73.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-31	yes	3.65
E-ANND-3	no	0.98

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

15 targets.

Target	Regulation
DLX5	Activation
FOS	Unknown
IL1A
IL2	Activation
MAPK1
NGF
PRKACA
PTHLH	Activation
RAB15	Activation
SAMD5	Activation
SERPINE2	Repression
SLC12A5
SYNPO	Activation
TNF	Activation
VGF

JASPAR motifs

Motif	Name	Family
MA0733.1	EGR4	Three-zinc finger Kruppel-related
MA0733.2	EGR4	Three-zinc finger Kruppel-related

JASPAR matrix evidence (PMIDs): PMID:7891721

miRNA regulators (miRDB)

39 targeting EGR4, 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-548AW	99.99	72.57	3559
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-889-5P	99.41	68.75	1025
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-548AS-3P	99.12	69.12	2294
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-4718	98.55	68.61	814
HSA-MIR-302F	98.44	69.02	1776

Literature-anchored findings (GeneRIF, showing 5)

• Data found multiple differences in gene expression between the high and low infertility risk groups, confirming the importance of an intact hypothalamo-pituitary testicular axis and EGR4 in fertility development (PMID:19828938)
• data suggest a tendency of gender-specific association of EGR2 and EGR4 in schizophrenia. (PMID:22691714)
• EGR4 directly transactivates specific variants (V3 and V4) of the PTHrP gene resulting in subsequent transactivation of the RANKL, IL-6 and IL-8 genes via paracrine action of the PTHrP protein. (PMID:25411851)
• this study is the first to screen the EGR4 gene in relation to male infertility. However, our findings did not clearly explain how nonsynonymous EGR4 variations affect spermatogenesis (PMID:28464846)
• our study demonstrated that the positive feedback loop between ZNF205-AS1 and EGR4 promotes non-small cell lung cancer (NSCLC) growth, and implied that targeting this feedback loop may be promising therapeutic strategy for NSCLC (PMID:30556283)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	egr1	ENSDARG00000037421
danio_rerio	egr2a	ENSDARG00000044098
danio_rerio	egr4	ENSDARG00000077799
mus_musculus	Egr4	ENSMUSG00000071341
rattus_norvegicus	Egr4	ENSRNOG00000015719
caenorhabditis_elegans		WBGENE00007772
caenorhabditis_elegans		WBGENE00043705

Paralogs (4): EGR1 (ENSG00000120738), EGR2 (ENSG00000122877), EGR3 (ENSG00000179388), WT1 (ENSG00000184937)

Protein

Protein identifiers

Early growth response protein 4 — Q05215 (reviewed: Q05215)

Alternative names: AT133

All UniProt accessions (3): A0A0C4DG96, B7ZKU3, Q05215

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator. Recognizes and binds to the DNA sequence 5’-GCGGGGGCG-3’ (GSG). Activates the transcription of target genes whose products are required for mitogenesis and differentiation.

Subcellular location. Nucleus.

Induction. By PHA/PMA or by serum.

Similarity. Belongs to the EGR C2H2-type zinc-finger protein family.

RefSeq proteins (1): NP_001956* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily

Pfam: PF00096

UniProt features (15 total): compositionally biased region 4, sequence conflict 4, zinc finger region 3, region of interest 3, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q05215-F1	51.89	0.02

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9031628	NGF-stimulated transcription

MSigDB gene sets: 118 (showing top): BENPORATH_ES_WITH_H3K27ME3, PEREZ_TP63_TARGETS, SATO_SILENCED_BY_DEACETYLATION_IN_PANCREATIC_CANCER, AREB6_01, CREBP1_Q2, NAGASHIMA_NRG1_SIGNALING_UP, CREB_Q4, SRF_01, IRF7_01, MODULE_120, MODULE_75, SRF_C, E4F1_Q6, MODULE_123, HELLER_HDAC_TARGETS_SILENCED_BY_METHYLATION_UP

GO Biological Process (3): regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of cell population proliferation (GO:0008284), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (10): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), zinc ion binding (GO:0008270), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (3): chromatin (GO:0000785), nucleoplasm (GO:0005654), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Nuclear Events (kinase and transcription factor activation)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
cellular anatomical structure	2
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
positive regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	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
transcription cis-regulatory region binding	1
transcription regulator activity	1
transition metal ion binding	1
DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
cation binding	1
chromosome	1
nuclear lumen	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1180 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EGR4	NAB1	Q13506	880
EGR4	NAB2	Q15742	844
EGR4	NPAS4	Q8IUM7	610
EGR4	NR4A1	P22736	528
EGR4	FOSL1	P15407	526
EGR4	NGF	P01138	525
EGR4	FOSB	P53539	519
EGR4	FOS	P01100	513
EGR4	FHL2	Q14192	489
EGR4	NR4A3	Q92570	462
EGR4	SLC12A5	Q9H2X9	428
EGR4	ZNF821	O75541	424
EGR4	CRH	P06850	414
EGR4	ETV2	O00321	413
EGR4	NFATC1	O95644	406

IntAct

7 interactions, top by confidence:

A	B	Type	Score
BAG3	EGR4	psi-mi:“MI:0915”(physical association)	0.560
EGR4	ABI2	psi-mi:“MI:0915”(physical association)	0.560
ABI2	EGR4	psi-mi:“MI:0915”(physical association)	0.000
BAG3	EGR4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (4): EGR4 (Reconstituted Complex), EGR4 (Reconstituted Complex), ABI2 (Two-hybrid), BAG3 (Two-hybrid)

ESM2 similar proteins: A0A0U1RRK4, A0A1W2PPE3, A0A1W2PR82, A0A2R8Y2Y2, A0A494C0N9, A0A494C0Y3, A0JNN8, A6NF83, A6NHQ4, A6QPM6, A8E4L3, A8MTW9, B2KGE5, C9JVW0, I3L1E1, O43541, O75474, O75638, P0C7X2, P70339, P89439, Q02080, Q05215, Q12950, Q3SYB3, Q5T230, Q5VV16, Q6NZ36, Q6NZY7, Q6P1X6, Q6VB84, Q6VUC0, Q6VUP9, Q6ZSJ8, Q7RTU5, Q7TNS8, Q80WY3, Q86SI9, Q86UU5, Q8K025

Diamond homologs: A1XSY8, A4II20, O73691, O73692, O73693, O73694, P08046, P08152, P08154, P11161, P18146, P26632, P26633, P26634, P26635, P31509, P43300, P43301, P51774, P80944, Q00453, Q00911, Q05159, Q05215, Q06889, Q08427, Q12132, Q18250, Q29419, Q29W20, Q6GQH4, Q6NTY6, Q9GL32, Q9WUF2, A1C6L9, A1DH89, A2QCJ9, B0XSK6, B8NGC8, O14335

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	118
Likely benign	7
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

225 predictions. Top by Δscore:

Variant	Effect	Δscore
2:73293176:CCTTA:C	donor_loss	0.9800
2:73293177:CTTA:C	donor_loss	0.9800
2:73293178:TTAC:T	donor_loss	0.9800
2:73293179:TA:T	donor_loss	0.9800
2:73293181:C:G	donor_loss	0.9800
2:73293180:ACCT:A	donor_gain	0.9700
2:73293181:CCTC:C	donor_gain	0.9700
2:73293181:CCT:C	donor_gain	0.9400
2:73293183:T:TA	donor_gain	0.9400
2:73293180:A:AC	donor_gain	0.9100
2:73293181:C:CC	donor_gain	0.9100
2:73292779:CTG:C	acceptor_gain	0.9000
2:73293212:C:A	donor_gain	0.9000
2:73293109:T:TA	donor_gain	0.8800
2:73292778:CCTG:C	acceptor_loss	0.8100
2:73292780:TGC:T	acceptor_loss	0.8100
2:73292781:GCTGA:G	acceptor_loss	0.8100
2:73292783:T:C	acceptor_loss	0.8100
2:73292782:C:CC	acceptor_gain	0.8000
2:73292784:G:C	acceptor_loss	0.7700
2:73293578:G:C	donor_gain	0.7600
2:73293573:A:AC	donor_gain	0.7500
2:73293090:G:C	donor_gain	0.7400
2:73292776:CGC:C	acceptor_gain	0.7300
2:73292959:A:T	donor_gain	0.7300
2:73293574:T:C	donor_gain	0.7300
2:73293069:C:A	donor_gain	0.7100
2:73293454:CCT:C	donor_gain	0.6900
2:73292777:GC:G	acceptor_loss	0.6800
2:73292778:CC:C	acceptor_loss	0.6800

AlphaMissense

3134 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:73291552:G:C	H559D	1.000
2:73291577:G:C	F550L	1.000
2:73291577:G:T	F550L	1.000
2:73291578:A:C	F550C	1.000
2:73291578:A:G	F550S	1.000
2:73291579:A:G	F550L	1.000
2:73291591:A:G	C546R	1.000
2:73291600:A:G	C543R	1.000
2:73291604:A:C	F541L	1.000
2:73291604:A:T	F541L	1.000
2:73291606:A:G	F541L	1.000
2:73291622:G:C	H535Q	1.000
2:73291622:G:T	H535Q	1.000
2:73291624:G:C	H535D	1.000
2:73291630:G:T	R533S	1.000
2:73291634:G:C	H531Q	1.000
2:73291634:G:T	H531Q	1.000
2:73291636:G:C	H531D	1.000
2:73291636:G:T	H531N	1.000
2:73291644:A:G	L528P	1.000
2:73291661:G:C	F522L	1.000
2:73291661:G:T	F522L	1.000
2:73291662:A:G	F522S	1.000
2:73291663:A:G	F522L	1.000
2:73291673:G:C	C518W	1.000
2:73291674:C:T	C518Y	1.000
2:73291675:A:G	C518R	1.000
2:73291682:G:C	C515W	1.000
2:73291684:A:G	C515R	1.000
2:73291688:G:C	F513L	1.000

dbSNP variants (sampled 300 via entrez): RS1000417794 (2:73293529 T>C,G), RS1000659971 (2:73294056 A>G), RS1000711853 (2:73293856 G>A,T), RS1002407715 (2:73290947 A>C), RS1002417252 (2:73291283 G>A), RS1002930377 (2:73294914 C>T), RS1003769269 (2:73295210 T>G), RS1004131930 (2:73291313 G>A,T), RS1004184200 (2:73291169 C>G,T), RS1004881804 (2:73295263 C>A), RS1005137660 (2:73292512 C>T), RS1005190122 (2:73292230 C>G,T), RS1005892293 (2:73294070 C>T), RS1007023132 (2:73292826 A>C,G), RS1008945507 (2:73290843 C>G,T)

Disease associations

OMIM: gene MIM:128992 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST003994_1	Age at voice drop	1.000000e-08
GCST006879_10	Blood metabolite levels	6.000000e-09
GCST006879_11	Blood metabolite levels	1.000000e-12
GCST006879_6	Blood metabolite levels	5.000000e-14
GCST006879_7	Blood metabolite levels	2.000000e-15
GCST006879_8	Blood metabolite levels	4.000000e-08
GCST006879_9	Blood metabolite levels	2.000000e-14
GCST90011892_2	Retinitis pigmentosa	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007888	age at voice drop

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
entinostat	affects cotreatment, decreases expression	2
Silicon Dioxide	increases expression	2
Valproic Acid	decreases expression, increases expression	2
bisphenol F	increases expression	1
methylmercuric chloride	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
cylindrospermopsin	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Zoledronic Acid	increases expression	1
Fulvestrant	increases methylation	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Aspirin	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	increases expression	1
Hydrogen Peroxide	affects expression	1
Lead	decreases expression	1
Methotrexate	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Plant Oils	increases expression	1
Quercetin	increases expression	1

Clinical trials (associated diseases)

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