ELF4

Summary

ELF4 (E74 like ETS transcription factor 4, HGNC:3319) is a protein-coding gene on chromosome Xq26.1, encoding ETS-related transcription factor Elf-4 (Q99607). Transcriptional activator that binds to DNA sequences containing the consensus 5’-WGGA-3'.

The protein encoded by this gene is a transcriptional activator that binds and activates the promoters of the CSF2, IL3, IL8, and PRF1 genes. The encoded protein is involved in natural killer cell development and function, innate immunity, and induction of cell cycle arrest in naive CD8+ cells. Two transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 2000 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autoinflammatory syndrome, familial, X-linked, Behcet-like 2 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 179 total — 7 pathogenic, 2 likely-pathogenic
• GTEx eGene: eQTL in 19 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 28
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 2 cancer types (inferred from mutation patterns)
• Transcription factor: yes — 55 downstream targets (CollecTRI)
• MANE Select transcript: NM_001421

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3319
Approved symbol	ELF4
Name	E74 like ETS transcription factor 4
Location	Xq26.1
Locus type	gene with protein product
Status	Approved
Aliases	MEF, ELFR
Ensembl gene	ENSG00000102034
Ensembl biotype	protein_coding
OMIM	300775
Entrez	2000

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

MANE Select: ENST00000308167

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 3: 1

ENST00000308167, ENST00000335997, ENST00000434609, ENST00000880884, ENST00000880885, ENST00000880886, ENST00000880887, ENST00000958346, ENST00001136189

RefSeq mRNA: 4 — MANE Select: NM_001421 NM_001127197, NM_001421, NM_001440765, NM_001440766

CCDS: CCDS14617

Canonical transcript exons

ENST00000308167 — 9 exons

Exon	Start	End
ENSE00001095261	130110325	130110497
ENSE00001095266	130074581	130074752
ENSE00001352919	130081256	130081539
ENSE00001614860	130072226	130072417
ENSE00001703639	130071336	130071419
ENSE00001789328	130071040	130071232
ENSE00001804899	130069300	130069677
ENSE00001843723	130063955	130067525
ENSE00002193981	130074049	130074141

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 95.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.8398 / max 490.1281, expressed in 1760 samples.

Highest expression (Bgee): endometrium epithelium, granulocyte, blood, leukocyte, mononuclear cell.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ELF4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 19 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

20 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Artery Tibial	eqtl	1.8e-16	-0.21	X:130108962:C:T
Esophagus Mucosa	eqtl	3.4e-14	+0.64	X:130111483:C:T
Thyroid	eqtl	3.3e-04	+0.34	X:131051931:C:T
Breast Mammary Tissue	eqtl	4.3e-04	-0.09	X:130131419:A:G
Muscle Skeletal	eqtl	8.4e-04	-0.09	X:130233463:G:A
Pancreas	eqtl	2.5e-03	+0.88	X:129547385:C:T
Brain Hippocampus	eqtl	2.6e-03	+0.68	X:130800261:A:G
Cells Cultured fibroblasts	eqtl	4.3e-03	+0.37	X:129779305:T:C
Spleen	eqtl	6.4e-03	+0.13	X:130194288:G:GC
Heart Left Ventricle	eqtl	8.6e-03	-0.39	X:129908757:C:T
Skin Not Sun Exposed Suprapubic	eqtl	9.5e-03	-0.42	X:129362228:A:G
Small Intestine Terminal Ileum	eqtl	1.5e-02	+0.22	X:129755410:G:A
Artery Aorta	eqtl	2.0e-02	-0.19	X:130108748:C:A
Brain Cortex	eqtl	2.0e-02	-1.20	X:130362631:C:T
Brain Caudate basal ganglia	eqtl	2.5e-02	+0.11	X:130379957:G:A
Skin Sun Exposed Lower leg	eqtl	2.5e-02	+0.27	X:130105641:C:CTT
Brain Cerebellum	eqtl	3.1e-02	+0.47	X:129768648:C:A
Skin Not Sun Exposed Suprapubic	sqtl	3.4e-02	-0.99	X:130217135:T:C
Whole Blood	eqtl	3.5e-02	-0.14	X:130089301:G:A
Brain Amygdala	eqtl	4.3e-02	+0.78	X:129227128:C:G

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
200459	14.2939	1604
200462	4.1055	1416
200463	1.8671	1087
200461	1.3945	703
200458	0.7665	214
200460	0.4122	233

Top tissues by expression

showing 100 of 279 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	95.22	gold quality
granulocyte	CL:0000094	94.32	gold quality
blood	UBERON:0000178	92.65	gold quality
leukocyte	CL:0000738	92.04	gold quality
mononuclear cell	CL:0000842	91.79	gold quality
monocyte	CL:0000576	91.77	gold quality
cartilage tissue	UBERON:0002418	90.34	gold quality
germinal epithelium of ovary	UBERON:0001304	89.67	gold quality
mucosa of transverse colon	UBERON:0004991	89.27	gold quality
colonic mucosa	UBERON:0000317	89.09	gold quality
ileal mucosa	UBERON:0000331	88.94	gold quality
jejunal mucosa	UBERON:0000399	88.85	gold quality
mucosa of sigmoid colon	UBERON:0004993	88.36	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.05	gold quality
parietal pleura	UBERON:0002400	87.59	gold quality
placenta	UBERON:0001987	87.37	gold quality
bone marrow	UBERON:0002371	87.23	gold quality
decidua	UBERON:0002450	87.02	gold quality
bone marrow cell	CL:0002092	86.95	gold quality
tibia	UBERON:0000979	86.73	gold quality
squamous epithelium	UBERON:0006914	86.44	gold quality
gingival epithelium	UBERON:0001949	86.43	gold quality
visceral pleura	UBERON:0002401	86.41	gold quality
pleura	UBERON:0000977	86.12	gold quality
esophagus squamous epithelium	UBERON:0006920	86.04	gold quality
cervix squamous epithelium	UBERON:0006922	85.67	gold quality
rectum	UBERON:0001052	85.60	gold quality
stromal cell of endometrium	CL:0002255	85.58	gold quality
amniotic fluid	UBERON:0000173	85.51	gold quality
mucosa of urinary bladder	UBERON:0001259	85.29	gold quality
epithelium of esophagus	UBERON:0001976	84.60	gold quality
lymph node	UBERON:0000029	84.43	gold quality
thymus	UBERON:0002370	84.25	gold quality
spleen	UBERON:0002106	84.22	gold quality
gingiva	UBERON:0001828	84.21	gold quality
trabecular bone tissue	UBERON:0002483	84.21	gold quality
duodenum	UBERON:0002114	84.11	gold quality
vermiform appendix	UBERON:0001154	84.05	gold quality
palpebral conjunctiva	UBERON:0001812	83.71	gold quality
epithelium of nasopharynx	UBERON:0001951	83.65	gold quality
transverse colon	UBERON:0001157	83.47	gold quality
upper lobe of left lung	UBERON:0008952	82.64	gold quality
upper lobe of lung	UBERON:0008948	82.58	gold quality
superficial temporal artery	UBERON:0001614	82.54	silver quality
body of stomach	UBERON:0001161	82.38	gold quality
caecum	UBERON:0001153	82.32	gold quality
small intestine Peyer’s patch	UBERON:0003454	82.17	gold quality
small intestine	UBERON:0002108	82.10	gold quality
urinary bladder	UBERON:0001255	81.49	gold quality
large intestine	UBERON:0000059	81.47	gold quality
right lung	UBERON:0002167	81.46	gold quality
intestine	UBERON:0000160	81.42	gold quality
colon	UBERON:0001155	81.42	gold quality
stomach	UBERON:0000945	81.31	gold quality
left ovary	UBERON:0002119	81.27	gold quality
tongue squamous epithelium	UBERON:0006919	81.14	silver quality
omental fat pad	UBERON:0010414	81.09	gold quality
peritoneum	UBERON:0002358	81.08	gold quality
right uterine tube	UBERON:0001302	81.06	gold quality
subcutaneous adipose tissue	UBERON:0002190	80.91	gold quality
layer of synovial tissue	UBERON:0007616	80.83	gold quality
lung	UBERON:0002048	80.77	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.72	gold quality
left uterine tube	UBERON:0001303	80.71	gold quality
esophagus mucosa	UBERON:0002469	80.65	gold quality
gall bladder	UBERON:0002110	80.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.48	gold quality
ovary	UBERON:0000992	80.45	gold quality
right ovary	UBERON:0002118	80.19	gold quality
ectocervix	UBERON:0012249	79.83	gold quality
skin of abdomen	UBERON:0001416	79.76	gold quality
right coronary artery	UBERON:0001625	79.60	gold quality
tonsil	UBERON:0002372	79.47	gold quality
smooth muscle tissue	UBERON:0001135	79.43	gold quality
lower lobe of lung	UBERON:0008949	79.32	gold quality
body of uterus	UBERON:0009853	79.32	gold quality
pylorus	UBERON:0001166	79.16	gold quality
myometrium	UBERON:0001296	79.15	gold quality
skin of leg	UBERON:0001511	79.12	gold quality
zone of skin	UBERON:0000014	79.10	gold quality
female reproductive system	UBERON:0000474	79.10	gold quality
colonic epithelium	UBERON:0000397	78.94	gold quality
fallopian tube	UBERON:0003889	78.81	gold quality
mucosa of stomach	UBERON:0001199	78.71	gold quality
hair follicle	UBERON:0002073	78.62	silver quality
sigmoid colon	UBERON:0001159	78.40	gold quality
tibial artery	UBERON:0007610	78.32	gold quality
popliteal artery	UBERON:0002250	78.31	gold quality
connective tissue	UBERON:0002384	78.24	gold quality
adipose tissue	UBERON:0001013	78.13	gold quality
uterine cervix	UBERON:0000002	78.10	gold quality
lower esophagus mucosa	UBERON:0035834	78.09	gold quality
metanephric glomerulus	UBERON:0004736	78.04	gold quality
esophagus	UBERON:0001043	77.90	gold quality
renal glomerulus	UBERON:0000074	77.81	gold quality
metanephros	UBERON:0000081	77.81	gold quality
fundus of stomach	UBERON:0001160	77.71	gold quality
vagina	UBERON:0000996	77.67	gold quality
uterus	UBERON:0000995	77.63	gold quality
aorta	UBERON:0000947	77.56	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.10

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	50.1	low
Placenta	tissue	22.3	low
Stomach 1	tissue	19.2	medium
Thymus	tissue	18.3
Urinary bladder	tissue	17.6	medium
Lymph node	tissue	17.1	not detected
Colon	tissue	17.0	medium
Tonsil	tissue	16.8	medium
Rectum	tissue	16.6	medium
Small intestine	tissue	16.0	medium
Spleen	tissue	15.7	low
Appendix	tissue	13.7	medium
Duodenum	tissue	13.4	medium
Lung	tissue	13.2	medium
Ovary	tissue	12.8	medium
Choroid plexus	tissue	12.2
Fallopian tube	tissue	11.4	medium
Smooth muscle	tissue	9.9	not detected
Locus coeruleus	tissue	9.9
Hippocampus	tissue	9.8	not detected
Nucleus accumbens	tissue	9.5
Skin 1	tissue	8.9	medium
Gallbladder	tissue	8.7	medium
Vagina	tissue	8.5	medium
Postcentral gyrus	tissue	8.5
Endometrium 1	tissue	8.3	low
Adipose tissue	tissue	7.9	not detected
Esophagus	tissue	6.8	medium
Cervix	tissue	6.6	medium
Parathyroid gland	tissue	4.5	medium
Seminal vesicle	tissue	3.9	medium
Pituitary gland	tissue	3.8
Breast	tissue	3.7	low
Prostate	tissue	3.4	medium
Tongue	tissue	3.3
Hypothalamus	tissue	3.1
Heart muscle	tissue	2.9	not detected
Substantia nigra	tissue	2.8
Kidney	tissue	2.8	medium
Spinal cord	tissue	2.8
Periaqueductal gray	tissue	2.8
Adrenal gland	tissue	2.7	medium
Liver	tissue	2.6	medium
Salivary gland	tissue	2.5	low
Septum	tissue	2.5
Testis	tissue	2.4	medium
Medulla oblongata	tissue	2.3
Pons	tissue	2.2
Corpus callosum	tissue	2.2
Superior colliculi	tissue	2.0
Pancreas	tissue	1.9	medium
Epididymis	tissue	1.9	medium
Midbrain	tissue	1.9
Skeletal muscle	tissue	1.8	not detected
Amygdala	tissue	1.8
Thalamus	tissue	1.7
Thyroid gland	tissue	1.7	low
Ventral forebrain	tissue	1.7
Putamen	tissue	1.6
Hippocampal formation	tissue	1.5

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Nucleus tractus solitarii (13.8), Temporal white matter (13.8), Centromedial thalamic nucleus (13.5), Area postrema (13.2), Corpus callosum, splenium (white matter) (13.2).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

showing 30 of 55 targets:

Target	Regulation
ABCB1
AGTR2
ALDOA
AQP2
CARM1
CCNG1
CD79A
CD8A
CD99
CDKN2A
CDKN2B
CHD7
CKM
CSF2	Activation
CXCL8	Activation
DEFB4A
DLX5	Repression
EIF3K
ELF4
FASLG
GZMB
HBD	Activation
IFNA2	Activation
IFNA8	Activation
IFNB1	Repression
IFNL3	Activation
IL17A
LGALS3
LTBP1
LUM

JASPAR motifs

Motif	Name	Family
MA0641.1	ELF4	Ets-related
UN0961.1	ELF4::TBX21	Ets-related,T-Box factors
UN0962.1	ELF4::TBX4	Ets-related,TBX2-related factors
UN0963.1	ELF4::TEAD3	Ets-related,TEF-1-related factors
UN0964.1	ELF4::TEAD4	Ets-related,TEF-1-related factors

JASPAR matrix evidence (PMIDs): PMID:20517297

Upstream regulators (CollecTRI, top): E2F1, ELF4, GFI1B, KDM6A, NPM1, SP1, TP53

miRNA regulators (miRDB)

Targeting ELF4 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 103 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4514	99.99	67.10	1870
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192

Functional genomics

Regional missense constraint (gnomAD)

ENST00000308167 splits into 4 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
X:130,066,724–130,069,510	260 / 269.2	0.97	no
X:130,069,511–130,071,212	35 / 84.0	0.42	no
X:130,071,213–130,074,106	88 / 92.4	0.95	no
X:130,074,107–130,081,330	35 / 76.4	0.46	no

Literature-anchored findings (GeneRIF, showing 28)

• Functional dissection of the transactivation mechanisms of the ETS transcription factor MEF (PMID:12151102)
• MEF is an important regulator of IL-8 expression (PMID:14625302)
• promyelocytic leukemia protein, but not Sp100, induced the accumulation of MEF in PML nuclear bodies and MEF and PML physically interacted, stimulating MEF transcriptional activity, resulting in the up-regulation of endogenous lysozyme expression. (PMID:14976184)
• MEF activated HBD2 promoter activity, and increased the endogenous HBD2 transcription level. The activated HBD2 promoter activity was attenuated by the antisense MEF RNA input and the loss of the ETS binding site in the HBD2 promoter (PMID:15013761)
• regulation in epithelial cells by Sp1 (PMID:15907486)
• RT-PCR analysis of RNA isolated from bone marrow samples from the patient demonstrates that the translocation occurs within intron 1 of ERG isoform 1 and intron 2 of ELF4 resulting in an in-frame fusion joining exon 2 from ELF4 with exon 2 of ERG. (PMID:16303180)
• Loss of ELF4 leads to increased quiescence in bone marrow endothelial cells by the deregulation of cyclin-dependent kinase-4 expression and to enhanced regeneration of sinusoidal blood vessels. (PMID:21350194)
• MEF is involved in PTH suppression of osteoblasts through activating the MKK4/JNK1 pathway and subsequently up-regulating Mab21l1 expression. (PMID:21465527)
• These studies implicate MEF as a previously unrecognized gatekeeper gene in gliomagenesis that promotes stem cell characteristics through Sox2 activation. (PMID:23217424)
• enhanced HDM2 expression induced by mutant NPM1 may have a role in MEF/ELF4-dependent leukemogenesis (PMID:23393136)
• The p53-MDM2-MEF axis is a feedback mechanism that exquisitely controls the balance of these transcriptional regulators. (PMID:25081543)
• The genes BCL6, NFE2, POU4F2 and ELF4 are primary 1,25(OH)2D3 targets in THP-1 cells (PMID:25482012)
• Overall, these data indicate that hypoxia or HIF-1alpha positively regulates MEF expression and function. (PMID:27040637)
• The decreased expression of miR-365 in human cervical cancer cells relieves its inhibitory effect on ELF4, which promotes the proliferation of cervical cancer cells and the formation of tumor. (PMID:31060678)
• ELF4 Is a Target of miR-124 and Promotes Neuroblastoma Proliferation and Undifferentiated State. (PMID:31624087)
• Hepatitis B Virus-Telomerase Reverse Transcriptase Promoter Integration Harnesses Host ELF4, Resulting in Telomerase Reverse Transcriptase Gene Transcription in Hepatocellular Carcinoma. (PMID:32170761)
• Elf4 regulates lysosomal biogenesis and the mTOR pathway to promote clearance of Staphylococcus aureus in macrophages. (PMID:33423322)
• High ELF4 expression in human cancers is associated with worse disease outcomes and increased resistance to anticancer drugs. (PMID:33836003)
• Human autoinflammatory disease reveals ELF4 as a transcriptional regulator of inflammation. (PMID:34326534)
• [ELF4 promotes proliferation and inhibits apoptosis of human insulinoma cells by activating Akt signaling]. (PMID:34658346)
• Loss of Function Mutation in ELF4 Causes Autoinflammatory and Immunodeficiency Disease in Human. (PMID:35266071)
• ELF4 is a critical component of a miRNA-transcription factor network and is a bridge regulator of glioblastoma receptor signaling and lipid dynamics. (PMID:35862252)
• An ELF4 hypomorphic variant results in NK cell deficiency. (PMID:36477361)
• A Multicenter Cohort Study of Immune Dysregulation Disorders Caused by ELF4 Variants in China. (PMID:36823308)
• FGF19-mediated ELF4 overexpression promotes colorectal cancer metastasis through transactivating FGFR4 and SRC. (PMID:36923538)
• ELF4 contributes to esophageal squamous cell carcinoma growth and metastasis by augmenting cancer stemness via FUT9. (PMID:37674363)
• Reciprocal regulation of lncRNA MEF and c-Myc drives colorectal cancer tumorigenesis. (PMID:38301392)
• A Novel Frameshift Variant of the ELF4 Gene in a Patient with Autoinflammatory Disease: Clinical Features, Transcriptomic Profiling and Functional Studies. (PMID:38773005)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Elf4	ENSMUSG00000031103
rattus_norvegicus	Elf4	ENSRNOG00000005352

Paralogs (28): ETV1 (ENSG00000006468), ETV7 (ENSG00000010030), SPI1 (ENSG00000066336), ETV2 (ENSG00000105672), ERF (ENSG00000105722), ELF2 (ENSG00000109381), ELK3 (ENSG00000111145), ETV3 (ENSG00000117036), ELF1 (ENSG00000120690), SPDEF (ENSG00000124664), ELK1 (ENSG00000126767), ETS1 (ENSG00000134954), EHF (ENSG00000135373), ELF5 (ENSG00000135374), ETV6 (ENSG00000139083), FLI1 (ENSG00000151702), GABPA (ENSG00000154727), ERG (ENSG00000157554), ETS2 (ENSG00000157557), ELK4 (ENSG00000158711), ELF3 (ENSG00000163435), FEV (ENSG00000163497), SPIC (ENSG00000166211), ETV4 (ENSG00000175832), ETV5 (ENSG00000244405), ETV3L (ENSG00000253831), ERFL (ENSG00000268041), SPIB (ENSG00000269404)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1928377) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 22 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal inflammatory response	1
abnormal definitive hematopoiesis	1
abnormal T cell differentiation	1
large lymphoid organs	1
increased susceptibility to viral infection	1
abnormal macrophage physiology	1
abnormal lymphocyte morphology	1
abnormal lymphocyte physiology	1
abnormal hematopoietic stem cell morphology	1
increased hematopoietic stem cell number	1
increased B cell number	1
impaired natural killer cell mediated cytotoxicity	1
decreased cytotoxic T cell cytolysis	1
increased B cell proliferation	1
increased T cell proliferation	1
decreased NK T cell number	1
decreased NK cell number	1
abnormal CD4-positive T cell differentiation	1
abnormal interferon level	1
abnormal interleukin level	1
abnormal tumor necrosis factor level	1
abnormal NK cell physiology	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
Drosophila melanogaster	P11536	99.8%	Diamond
Pan paniscus	A1YG61	99.7%	Diamond
Pan troglodytes	A2T737	99.7%	Diamond
Gorilla gorilla gorilla	A1YF15	99.6%	Diamond
Gallus gallus	P13474	99.5%	Diamond
Xenopus laevis	P18755	98.5%	Diamond
Bos taurus	Q2KIC2	98.1%	Diamond
Ateles geoffroyi	A2D4Z7	97.5%	Diamond
Lytechinus variegatus	P29773	93.8%	Diamond
Caenorhabditis elegans	Q18579	87.2%	Diamond
Danio rerio	Q9PUQ1	82.7%	Diamond
Drosophila virilis	Q7M3M6	79.6%	Diamond
Avian leukemia virus e26	P01105	99.4%	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
UTP14A	protein-coding	10813
ZDHHC9	protein-coding	51114
BCORL1	protein-coding	63035
RAB33A	protein-coding	9363
AIFM1	protein-coding	9131
ZNF280C	protein-coding	55609

Protein

Protein identifiers

ETS-related transcription factor Elf-4 — Q99607 (reviewed: Q99607)

Alternative names: E74-like factor 4, Myeloid Elf-1-like factor

All UniProt accessions (2): Q99607, B1AL80

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator that binds to DNA sequences containing the consensus 5’-WGGA-3’. Transactivates promoters of the hematopoietic growth factor genes CSF2, IL3, IL8, and of the bovine lysozyme gene. Acts synergistically with RUNX1 to transactivate the IL3 promoter. Transactivates the PRF1 promoter in natural killer (NK) cells and CD8+ T cells. Plays a role in the development and function of NK and NK T-cells and in innate immunity. Controls the proliferation and homing of CD8+ T-cells via the Kruppel-like factors KLF4 and KLF2. Controls cell senescence in a p53-dependent manner. Can also promote cellular transformation through inhibition of the p16 pathway. Is a transcriptional regulator of inflammation, controlling T-helper 17 (Th17) cells and macrophage inflammatory responses. Required for sustained transcription of anti-inflammatory genes, including IL1RN. Is a negative regulator of pro-inflammatory cytokines expression including IL17A, IL1B, IL6, TNFA and CXCL1. Down-regulates expression of TREM1, a cell surface receptor involved in the amplification of inflammatory responses.

Subunit / interactions. Interacts with RUNX1 (via the Runt domain); the interaction transactivates the IL3 promoter. Interacts (via its C-terminus) with PML; the interaction translocates ELF4 to PML nuclear bodies and enhances transactivation of LYZ.

Subcellular location. Nucleus. PML body.

Tissue specificity. Abundantly expressed in the placenta and in a variety of myeloid leukemia cell lines. Moderate levels of expression in heart, lung, spleen, thymus, peripheral blood lymphocytes, ovary and colon. Lower levels of expression in Jurkat T-cells and other T-cell lines and no expression in brain.

Disease relevance. A chromosomal aberration involving ELF4 has been found in a case of acute myeloid leukemia (AML). Translocation t(X;21)(q25-26;q22) with ERG. Autoinflammatory syndrome, familial, X-linked, Behcet-like 2 (AIFBL2) [MIM:301074] An X-linked recessive, autoinflammatory disorder characterized by ulceration of the oral mucosa and skin inflammation. Additional variable features may include gastrointestinal ulceration, arthritis, recurrent fevers, and iron deficiency anemia. Disease onset is in early childhood. The disease is caused by variants affecting the gene represented in this entry.

Induction. By ponisterone A in erythroleukemia cells.

Similarity. Belongs to the ETS family.

RefSeq proteins (4): NP_001120669, NP_001412, NP_001427694, NP_001427695 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000418	Ets_dom	Domain
IPR022084	TF_Elf_N	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR046328	ETS_fam	Family

Pfam: PF00178, PF12310

UniProt features (42 total): sequence variant 14, mutagenesis site 8, region of interest 6, compositionally biased region 5, modified residue 4, sequence conflict 2, chain 1, DNA-binding region 1, site 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99607-F1	49.77	0.13

Human Protein Atlas

Protein class: Predicted intracellular proteins, Transcription factors, Helix-turn-helix domains, Cancer-related genes, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nuclear bodies; nucleoplasm

Antibody reliability (HPA): IH enhanced · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1)

Position	Role
25–26	breakpoint for translocation to form elf4-erg oncogene

Post-translational modifications (4)

Type	Positions
Phosphoserine	151, 188, 641, 648

Mutagenesis-validated functional residues (8)

Position	Phenotype
211	loss of transcriptional activity shown in ifnb1 promoter-driven luciferase assay.
212	loss of transcriptional activity shown in ifnb1 promoter-driven luciferase assay.
219	loss of transcriptional activity shown in ifnb1 promoter-driven luciferase assay.
239	loss of transcriptional activity shown in ifnb1 promoter-driven luciferase assay.
251	loss of transcriptional activity shown in ifnb1 promoter-driven luciferase assay. loss of infb1 promoter binding. does not bind gpr35 …
252	loss of transcriptional activity shown in ifnb1 promoter-driven luciferase assay.
255	loss of transcriptional activity shown in ifnb1 promoter-driven luciferase assay.
260	loss of transcriptional activity shown in ifnb1 promoter-driven luciferase assay.

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: 373 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, YAATNRNNNYNATT_UNKNOWN, ACTACCT_MIR196A_MIR196B, GNF2_MSN, GOBP_NEGATIVE_REGULATION_OF_INTERLEUKIN_1_PRODUCTION, GNF2_BNIP2, GOBP_INFLAMMATORY_RESPONSE, GGGNRMNNYCAT_UNKNOWN, LFA1_Q6, MODULE_45, GENTILE_RESPONSE_CLUSTER_D3, AP4_Q6, CROONQUIST_NRAS_SIGNALING_UP, TGACCTY_ERR1_Q2, TAL1ALPHAE47_01

GO Biological Process (12): natural killer cell proliferation (GO:0001787), NK T cell proliferation (GO:0001866), DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), cell differentiation (GO:0030154), negative regulation of interleukin-1 beta production (GO:0032691), negative regulation of interleukin-6 production (GO:0032715), negative regulation of tumor necrosis factor production (GO:0032720), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of inflammatory response (GO:0050728), regulation of DNA-templated transcription (GO:0006355)

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), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nuclear body (GO:0016604), PML body (GO:0016605)

GO top-level categories

48 GO namespaces:

Category	Terms
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
natural killer cell activation	1
lymphocyte proliferation	1
alpha-beta T cell proliferation	1
NK T cell activation	1
gene expression	1
RNA biosynthetic process	1
cellular developmental process	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
negative regulation of interleukin-1 production	1
negative regulation of cytokine production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
negative regulation of tumor necrosis factor superfamily cytokine production	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
regulation of gene expression	1
regulation of RNA biosynthetic process	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
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
binding	1
DNA binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1
nucleoplasm	1
intracellular membraneless organelle	1
nuclear body	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 11 of 24 annotations. The rest are phylogenetic / computational / electronic (IEA).

11 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of inflammatory response	BP	mutant phenotype
negative regulation of interleukin-1 beta production	BP	mutant phenotype
negative regulation of interleukin-6 production	BP	mutant phenotype
negative regulation of tumor necrosis factor production	BP	mutant phenotype
positive regulation of DNA-templated transcription	BP	direct assay
positive regulation of transcription by RNA polymerase II	BP	direct assay
PML body	CC	direct assay
nuclear body	CC	direct assay
DNA-binding transcription activator activity, RNA polymerase II-specific	MF	direct assay
RNA polymerase II cis-regulatory region sequence-specific DNA binding	MF	direct assay
sequence-specific double-stranded DNA binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 664 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ELF4	KLF2	Q9Y5W3	656
ELF4	PRR9	Q5T870	606
ELF4	PRR7	Q8TB68	597
ELF4	KLF4	P78338	567
ELF4	ELF3	P78545	540
ELF4	SELL	P14151	537
ELF4	CCR7	P32248	462
ELF4	LRRC30	A6NM36	454
ELF4	IL2RB	P14784	449
ELF4	MAVS	Q7Z434	449
ELF4	TBK1	Q9UHD2	441
ELF4	CD44	P16070	419
ELF4	IL3	P08700	416
ELF4	CSF2	P04141	414
ELF4	PRR5	P85299	397

IntAct

Human interaction partners of ELF4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

8 partners by confidence:

Partner	Interaction type	MIscore	Records
RUNX1	physical association	0.400	1
CASP4	physical association	0.370	1
NFE2L2	physical association	0.370	1
ORF10	physical association	0.370	1
S	physical association	0.370	1
SET	physical association	0.370	1
FLOT1	association	0.350	1
SMCHD1	proximity	0.270	1

BioGRID (120 interactions; top human partners by supporting records): NPM1 (Affinity Capture-Western; 3 records), MDM2 (Affinity Capture-Western; 2 records), PML (Affinity Capture-Western; 2 records), RUNX1 (Affinity Capture-Western; 2 records), SKP2 (Biochemical Activity; 2 records), ACTR5 (Proximity Label-MS), ACTR6 (Proximity Label-MS), ACTR8 (Proximity Label-MS), AGO2 (Affinity Capture-RNA), ARID2 (Proximity Label-MS), ARID4B (Proximity Label-MS), ASH2L (Proximity Label-MS), ASXL1 (Proximity Label-MS), ASXL2 (Proximity Label-MS), ATF7IP (Proximity Label-MS)

SIGNOR signaling

8 signaling interactions:

A	Effect	B	Mechanism
ELF4	“up-regulates quantity by expression”	CXCL8	“transcriptional regulation”
ELF4	“up-regulates quantity by expression”	LYZ	“transcriptional regulation”
ELF4	“up-regulates quantity by expression”	MDM2	“transcriptional regulation”
E2F1	“up-regulates quantity by expression”	ELF4	“transcriptional regulation”
KDM6A	“down-regulates quantity by repression”	ELF4	“transcriptional regulation”
ATM	“down-regulates activity”	ELF4	phosphorylation
TBK1	“up-regulates activity”	ELF4	phosphorylation
ELF4	“form complex”	ELF4/RUNX1	binding

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 2 cancer types — AML, LGGNOS.

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for ELF4: 179 ClinVar records (9 pathogenic / likely pathogenic); 1 GWAS association. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	2
Uncertain significance	64
Likely benign	20
Benign	4

Top pathogenic / likely-pathogenic (9)

Showing all 9 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
4470621	NM_001421.4(ELF4):c.985C>T (p.Arg329Ter)	Pathogenic	criteria provided, single submitter	3
4281530	NM_001421.4(ELF4):c.521_525del (p.Lys173_Ser174insTer)	Pathogenic	criteria provided, single submitter	1
4282459	NM_001421.4(ELF4):c.700C>T (p.Arg234Ter)	Pathogenic	criteria provided, single submitter	1
2504297	NM_001421.4(ELF4):c.553C>T (p.Arg185Ter)	Likely pathogenic	criteria provided, single submitter	1
4874700	NM_001421.4(ELF4):c.1336_1337del (p.Ser446fs)	Likely pathogenic	criteria provided, single submitter	1
4848750	NC_000023.10:g.(?129197929)(129215514_129244299)del	Pathogenic	criteria provided, single submitter	1
1676293	NM_001421.4(ELF4):c.752G>C (p.Trp251Ser)	Pathogenic	no assertion criteria provided	1
1676294	NM_001421.4(ELF4):c.1015del (p.Ala339fs)	Pathogenic	no assertion criteria provided	1
1676295	NM_001421.4(ELF4):c.691T>C (p.Trp231Arg)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ELF4’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 39 predictions of 801):

Position(s)	Effect	Δscore	Sites
X:130069298–130069299	donor_loss	1.0000	5
X:130069679	acceptor_loss	1.0000	3
X:130071038–130071039	donor_loss	1.0000	5
X:130071093	donor_gain	1.0000
X:130071233–130071234	acceptor_loss	1.0000	6
X:130071334–130071335	donor_loss	1.0000	5
X:130072224–130072225	donor_loss	1.0000	4
X:130072261	donor_gain	1.0000
X:130072418–130072419	acceptor_loss	1.0000	6
X:130074155–130074156	acceptor_gain	1.0000	3

AlphaMissense

912 missense substitutions predicted likely pathogenic (of 4,284 scored), across 195 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M260	9	0.999	1.000
M265	9	0.992	1.000
M293	9	0.904	0.993
F239	8	1.000	1.000
F290	8	0.999	1.000
F214	8	0.993	1.000
N261	8	0.993	1.000
D243	8	0.983	0.999
D221	8	0.980	0.998
N256	8	0.974	0.998
D259	8	0.956	0.993
F12	8	0.880	0.973
W212	7	1.000	1.000
W231	7	1.000	1.000
W251	7	1.000	1.000
E263	7	0.999	1.000
R285	7	0.997	1.000
I277	7	0.994	1.000
C225	7	0.991	1.000
K280	7	0.991	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:300775 | disease phenotypes: MIM:301074

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
autoinflammatory syndrome, familial, X-linked, Behcet-like 2	Strong	X-linked
short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia	Supportive	X-linked

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
autoinflammatory syndrome, familial, X-linked, Behcet-like 2	Definitive	XL

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (2 panels, 2 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

2 panels:

Panel	Rating
Autoinflammatory disorders	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green

Mondo (2): autoinflammatory syndrome, familial, X-linked, Behcet-like 2 (MONDO:0024770), short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia (MONDO:0018967)

Orphanet (1): X-linked immune dysregulation with inflammatory bowel disease due to ELF4 deficiency (Orphanet:676125)

HPO phenotypes

28 phenotypes (HPO-id order):

HPO	Term
HP:0000155	Oral ulcer
HP:0000988	Skin rash
HP:0001369	Arthritis
HP:0001419	X-linked recessive inheritance
HP:0001824	Weight loss
HP:0001891	Iron deficiency anemia
HP:0001894	Thrombocytosis
HP:0001945	Fever
HP:0001954	Recurrent fever
HP:0002014	Diarrhea
HP:0002027	Abdominal pain
HP:0002037	Inflammation of the large intestine
HP:0002205	Recurrent respiratory infections
HP:0002583	Colitis
HP:0003565	Elevated erythrocyte sedimentation rate
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0005218	Anoperineal fistula
HP:0005231	Chronic gastritis
HP:0009789	Perianal abscess
HP:0011227	Elevated circulating C-reactive protein concentration
HP:0011463	Childhood onset
HP:0012450	Chronic constipation
HP:0030374	Decreased memory B cell proportion
HP:0030783	Increased circulating interleukin 6 concentration
HP:0040218	Reduced total natural killer cell count
HP:0100633	Esophagitis
HP:0100827	Increased total lymphocyte count

GWAS associations

1 associations:

Study	Trait	p-value
GCST008103_137	Bipolar disorder	5e-6

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	7
Benzo(a)pyrene	affects methylation, increases expression	6
Tetrachlorodibenzodioxin	decreases reaction, increases expression	5
Tretinoin	increases expression, decreases expression	4
Cyclosporine	increases expression	3
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	increases expression, increases methylation	2
Cadmium Chloride	decreases expression, increases abundance	2
FR900359	increases phosphorylation	1
dicrotophos	increases expression	1
chloroacetaldehyde	increases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
9,10-dihydro-9,10-dihydroxybenzo(a)pyrene	increases expression	1
benzo(e)pyrene	decreases methylation	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	decreases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1

Cellosaurus cell lines

5 cell lines: 3 embryonic stem cell, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A1H5	SEES3-1V human ELF4, clone1	Embryonic stem cell	Male
CVCL_A1H6	SEES3-1V human ELF4, clone2	Embryonic stem cell	Male
CVCL_A1H7	SEES3-1V human ELF4, clone3	Embryonic stem cell	Male
CVCL_E1MY	HyCyte THP-1 KO-hELF4	Cancer cell line	Male
CVCL_F4HZ	HyCyte THP-1 KO-hTRAF2 and hTRAF2	Cancer cell line	Male

Clinical trials (associated diseases)

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