E2F4

Summary

E2F4 (E2F transcription factor 4, HGNC:3118) is a protein-coding gene on chromosome 16q22.1, encoding Transcription factor E2F4 (Q16254). Transcription activator that binds DNA cooperatively with DP proteins through the E2 recognition site, 5’-TTTC[CG]CGC-3’ found in the promoter region of a number of genes whose products are involved in cell cycle regulation or in DNA replication.

The protein encoded by this gene is a member of the E2F family of transcription factors. The E2F family plays a crucial role in the control of cell cycle and action of tumor suppressor proteins and is also a target of the transforming proteins of small DNA tumor viruses. The E2F proteins contain several evolutionally conserved domains found in most members of the family. These domains include a DNA binding domain, a dimerization domain which determines interaction with the differentiation regulated transcription factor proteins (DP), a transactivation domain enriched in acidic amino acids, and a tumor suppressor protein association domain which is embedded within the transactivation domain. This protein binds to all three of the tumor suppressor proteins pRB, p107 and p130, but with higher affinity to the last two. It plays an important role in the suppression of proliferation-associated genes, and its gene mutation and increased expression may be associated with human cancer.

Source: NCBI Gene 1874 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 67 total
• Druggable target: yes
• Transcription factor: yes — 274 downstream targets (CollecTRI)
• MANE Select transcript: NM_001950

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3118
Approved symbol	E2F4
Name	E2F transcription factor 4
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	E2F-4
Ensembl gene	ENSG00000205250
Ensembl biotype	protein_coding
OMIM	600659
Entrez	1874

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 12 protein_coding, 7 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000379378, ENST00000561904, ENST00000563238, ENST00000564718, ENST00000565226, ENST00000565849, ENST00000566368, ENST00000567007, ENST00000567228, ENST00000568485, ENST00000568693, ENST00000568839, ENST00000569573, ENST00000902238, ENST00000902239, ENST00000914909, ENST00000914910, ENST00000914911, ENST00000914912, ENST00000914913, ENST00000914914, ENST00000957227, ENST00000957228

RefSeq mRNA: 1 — MANE Select: NM_001950 NM_001950

CCDS: CCDS32464

Canonical transcript exons

ENST00000379378 — 10 exons

Exon	Start	End
ENSE00001480731	67198008	67198918
ENSE00001480751	67192155	67192362
ENSE00003474413	67194686	67194980
ENSE00003484374	67192761	67192870
ENSE00003533534	67197599	67197646
ENSE00003580299	67195782	67196006
ENSE00003613703	67193009	67193170
ENSE00003630514	67194398	67194459
ENSE00003631198	67197867	67197911
ENSE00003664622	67193472	67193515

Expression profiles

Bgee: expression breadth ubiquitous, 182 present calls, max score 98.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.5337 / max 248.4952, expressed in 1800 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154596	13.4583	1800
154599	0.0694	16
154600	0.0060	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	98.17	silver quality
ileal mucosa	UBERON:0000331	96.72	silver quality
granulocyte	CL:0000094	96.34	gold quality
left uterine tube	UBERON:0001303	96.14	gold quality
adenohypophysis	UBERON:0002196	95.97	gold quality
transverse colon	UBERON:0001157	95.86	gold quality
mucosa of transverse colon	UBERON:0004991	95.78	gold quality
metanephros cortex	UBERON:0010533	95.73	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.62	gold quality
apex of heart	UBERON:0002098	95.51	gold quality
body of stomach	UBERON:0001161	95.49	gold quality
tibialis anterior	UBERON:0001385	95.41	silver quality
right lobe of thyroid gland	UBERON:0001119	95.24	gold quality
upper lobe of left lung	UBERON:0008952	95.09	gold quality
body of uterus	UBERON:0009853	95.01	gold quality
lower esophagus mucosa	UBERON:0035834	95.01	gold quality
lower esophagus	UBERON:0013473	94.89	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.89	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.85	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.83	gold quality
left lobe of thyroid gland	UBERON:0001120	94.82	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.78	gold quality
monocyte	CL:0000576	94.53	gold quality
left adrenal gland cortex	UBERON:0035825	94.53	gold quality
omental fat pad	UBERON:0010414	94.52	gold quality
left adrenal gland	UBERON:0001234	94.47	gold quality
peritoneum	UBERON:0002358	94.45	gold quality
leukocyte	CL:0000738	94.42	gold quality
mononuclear cell	CL:0000842	94.37	gold quality
right ovary	UBERON:0002118	94.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-112	yes	41.16
E-ANND-3	yes	7.78

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

274 targets.

Target	Regulation
ACTG1	Unknown
ACTR5	Unknown
ADARB1	Unknown
AKR7A2	Unknown
ALDH5A1	Unknown
ALG5
ANAPC15	Unknown
ANLN	Unknown
APRT	Unknown
AR	Unknown
ASF1B	Activation
AURKB	Unknown
BACH1	Unknown
BARD1	Unknown
BCL11A	Unknown
BIRC5	Unknown
BORA	Unknown
BRCA1	Activation
BUB3	Unknown
C5orf22
CALM1	Unknown
CALR	Unknown
CAV1	Unknown
CBX5	Unknown
CCNA2	Unknown
CCNB1	Unknown
CCNB2	Repression
CCND1	Unknown
CCNE1	Repression
CDC25A	Activation

JASPAR motifs

Motif	Name	Family
MA0470.1	E2F4	E2F
MA0470.2	E2F4	E2F
MA0470.3	E2F4	E2F

JASPAR matrix evidence (PMIDs): PMID:17908821, PMID:18836037

Upstream regulators (CollecTRI, top): HCFC1, RBL2, TFDP3, TP53, TRIM28, ZBTB7A

miRNA regulators (miRDB)

32 targeting E2F4, 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-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-520F-5P	99.34	70.40	1632
HSA-MIR-190B-3P	99.33	68.29	1382
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-548L	99.06	70.90	2560
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-6889-3P	98.84	67.35	1198
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-6529-3P	98.68	66.76	1020
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-6868-3P	98.63	69.64	2259
HSA-MIR-4252	98.45	66.37	987
HSA-MIR-6804-5P	98.39	65.77	1084
HSA-MIR-8057	97.64	66.54	897
HSA-MIR-9851-5P	97.57	67.49	1067
HSA-MIR-4313	97.18	63.15	420
HSA-MIR-1913	97.07	66.20	1417
HSA-MIR-6822-3P	96.60	66.06	680

Literature-anchored findings (GeneRIF, showing 40)

• expression reduced in primary and metastatic breast carcinoma (PMID:11759817)
• regulation of expression of p130, p107 and E2F-4 in human cells (PMID:12006580)
• data point to Tat as an adaptor protein that recruits cellular factors such as E2F-4 to exert its multiple biological activities (PMID:12055184)
• Mutations in E2F-4 gene is associated with hereditary non-polyposis colorectal cancer (PMID:12148576)
• We investigated occupancy of ER-alpha promoter by pRb2/p130-E2F4/5-HDAC1-SUV39 H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1 complexes, and provided a link between pRb2/p130 and chromatin-modifying enzymes in the regulation of ER-alpha transcription (PMID:12789259)
• EBV LMP1 blocks p16INK4 pathway by promoting nuclear export of E2F-4. (PMID:12860972)
• Increased E2F4/p130 complex formation seen after irradiation depended on increased nuclear E2F4, dissociation of p130 from Cdk2, and p130 dephosphorylation. E2F4 siRNA prevented p130/E2F4 formation and sensitized cells to radiation-induced apoptosis. (PMID:15231644)
• E2F-a and E2F-c binding sites are involved in the TCR-induced down-regulation of ICBP90 gene transcription (PMID:15964557)
• E2F4 is a transcriptional regulator of the cell cycle genes. (PMID:16135806)
• There were no significant changes of CDK4 and E2F-1/4 expression in benzo(a)pyrene treated embryo lung fibroblasts. (PMID:16758952)
• Hypoxia induces substantial p130 dephosphorylation and nuclear accumulation, leading to the formation of E2F4/p130 complexes and increased occupancy of E2F4 and p130 at the RAD51 and BRCA1 promoters. (PMID:17001309)
• in response to radiation, E2F4 becomes active in the nucleus, enforces a stable G(2) arrest by target gene repression, and thus provides increased cell survival ability by minimizing propagation of cells that have irreparable DNA damage (PMID:17043659)
• Wnt/beta-catenin signaling may contribute to colorectal carcinogenesis by reducing the level of the E2F4 cell cycle repressor via an antisense mechanism (PMID:17121828)
• By interacting with p130, E2F4 plays a key role in the maintenance of a stable G2 arrest. Increased E2F4 levels and its translocation to the nucleus following genotoxic stress result in downregulation of mitotic genes. (PMID:17507799)
• Evolutionarily conserved multisubunit protein complex that contains p130 and E2F4 mediates the repression of cell cycle-dependent genes in quiescence. (PMID:17531812)
• deregulated nuclear E2F4 expression induces apoptosis via multiple pathways in normal intestinal epithelial cells but not in colon cancer cells. (PMID:17656449)
• E2F4, binding sites are located within 2 kb of a transcription start site, in both normal and tumor cells (PMID:17908821)
• Cell cycle genes are the evolutionarily conserved targets of the E2F4 transcription factor (PMID:17957245)
• FBI-1 is the first transcriptional repressor shown to act as a dual regulator in adipogenesis exerting repressor activities on target genes by both, direct and indirect mechanisms. (PMID:18368381)
• E2F4, PHACTR3, PRAME family member and CDH12 most probably play important role in non-small-cell lung cancer geneses (PMID:19473719)
• E2F4 may be determinant in the promotion of proliferation of human intestinal epithelial crypt cells and colorectal cancer cells. (PMID:19562678)
• Our data indicate that E2F4 is required for cardiomyocyte proliferation and suggest a function for E2F4 in mitosis (PMID:19955219)
• Tamoxifen resistant tumors displayed enriched expression of genes related to cell cycle and proliferation, as well as elevated activity of E2F transcription factors. (PMID:21789246)
• Silica could induce the high expression of cyclin D1 and CDK4 and the low expression of E2F-4, resulting in the cell cycle changes by AP-1/cyclin D1 pathway in human embryonic lung fibroblasts. (PMID:22357515)
• data demonstrate that enforced E2F4 expression in Burkitt lymphoma (BL) cells not only diminishes E2F1 levels, but also reduces selectively the tumorigenic properties and proliferation of BL cells (PMID:22475873)
• The inverse immunohistochemical relationship between E2F1 and E2F4 indicates a possible mechanistic interlink in colorectal cancer. (PMID:22688350)
• the loss of CDH1/E2F4 may be associated with worse clinical and pathological findings in mammary ductal carcinoma. (PMID:23007606)
• Short alleles (<13 repeats) of (AGC)n in E2F4 were less frequent in women with breast cancer than in the control sample. (PMID:23015403)
• Trim28 regulates cell proliferation by bridging HDAC1 and E2F3 and E2F4 interactions. (PMID:23060449)
• In terminally differentiated cells, common KDM5A and E2F4 gene targets were bound by the pRB-related protein p130, a DREAM complex component. (PMID:23093672)
• E2F4 promoter occupancy is globally associated with p53-repression targets, but not with p53 activation targets. (PMID:24096481)
• cancer-associated E2F4 mutations enhance the capacity of colorectal cancer cells to grow without anchorage, thereby contributing to tumor progression. (PMID:24100580)
• Analysis data from a panel of cell cycle transcription factors (E2F1, E2F4, E2F6, and GABPA) finds that a set of core cell cycle genes regulated in both U2OS and HeLa cells are bound by multiple cell cycle transcription factors. (PMID:24109597)
• Authors show that BRCA1 and RAD17 genes, whose derived proteins play a pivotal role in DNA damage repair, are transcriptional targets of gain-of-function mutant p53 proteins. (PMID:25650659)
• Data suggest that aberrant cell cycle activation in Ewing sarcoma is due to the de-repression of transcription factor E2F targets of transcriptional induction and physical recruitment of E2F3 by fusion protein EWS-FLI1 replacing E2F4 on their promoters. (PMID:25712098)
• This study found evidence that the number of triplet AGC repeats in the E2F4 gene may play a role in the susceptibility to early-onset colorectal cancer. (PMID:26343152)
• cell cycle-dependent transcription of the TRAIP gene by E2F1, E2F2, and E2F4 and rapid protein degradation leads to cell cycle-dependent expression with a maximum in G2/M (PMID:26369285)
• PHF8 reduces the H3K9me2 level at the E2F4 transcriptional start site, demonstrating a direct function of PHF8 in endothelial E2F4 gene regulation (PMID:26751588)
• Integrative genomic analyses confirm that E2F4 or E2F1 expression level is high in liposarcoma patients which associate with unfavorable prognosis. (PMID:26856934)
• The authors found that phosphorylation of residues S650 and S975 in p107 weakens the E2F4 transactivation domain binding. (PMID:27567532)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	e2f4	ENSDARG00000101578
mus_musculus	E2f4	ENSMUSG00000014859
rattus_norvegicus	E2f4	ENSRNOG00000015708

Paralogs (7): E2F2 (ENSG00000007968), E2F1 (ENSG00000101412), E2F3 (ENSG00000112242), E2F8 (ENSG00000129173), E2F5 (ENSG00000133740), E2F7 (ENSG00000165891), E2F6 (ENSG00000169016)

Protein

Protein identifiers

Transcription factor E2F4 — Q16254 (reviewed: Q16254)

All UniProt accessions (5): Q16254, H3BMP3, H3BTM3, H3BVE4, I3L1B6

UniProt curated annotations — full annotation on UniProt →

Function. Transcription activator that binds DNA cooperatively with DP proteins through the E2 recognition site, 5’-TTTC[CG]CGC-3’ found in the promoter region of a number of genes whose products are involved in cell cycle regulation or in DNA replication. The DRTF1/E2F complex functions in the control of cell-cycle progression from G1 to S phase. E2F4 binds with high affinity to RBL1 and RBL2. In some instances can also bind RB1. Specifically required for multiciliate cell differentiation: together with MCIDAS and E2F5, binds and activate genes required for centriole biogenesis.

Subunit / interactions. Component of the DRTF1/E2F transcription factor complex. Binds cooperatively with TFDP1/Dp-1 to E2F sites. The E2F4/TFDP1 dimer interacts preferentially with pocket protein RBL1, which inhibits the E2F transactivation domain. Lower affinity interaction has been found with retinoblastoma protein RB1. Interacts with TRRAP, which probably mediates its interaction with histone acetyltransferase complexes, leading to transcription activation. Interacts with HCFC1. Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, TFDP1 and TFDP2. The complex exists in quiescent cells where it represses cell cycle-dependent genes. It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2. Interacts with PML (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4 and isoform PML-5). Interacts with CEBPA (when phosphorylated).

Subcellular location. Nucleus.

Tissue specificity. Found in all tissue examined including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.

Post-translational modifications. Differentially phosphorylated in vivo.

Polymorphism. The poly-Ser region of E2F4 is polymorphic and the number of Ser varies in the population (from 8 to 17). The variation might be associated with tumorigenesis.

Similarity. Belongs to the E2F/DP family.

RefSeq proteins (1): NP_001941* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003316	E2F_WHTH_DNA-bd_dom	Domain
IPR015633	E2F	Family
IPR032198	E2F_CC-MB	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR037241	E2F-DP_heterodim	Homologous_superfamily

Pfam: PF02319, PF16421

UniProt features (36 total): strand 9, helix 6, region of interest 6, compositionally biased region 3, turn 3, short sequence motif 2, modified residue 2, sequence variant 2, initiator methionine 1, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5TUU	X-RAY DIFFRACTION	2.25
1CF7	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16254-F1	65.56	0.23

Functional residue map

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

Post-translational modifications (2): 2, 384

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-1362277	Transcription of E2F targets under negative control by DREAM complex
R-HSA-1362300	Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1
R-HSA-1538133	G0 and Early G1
R-HSA-2173796	SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-HSA-6804114	TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest
R-HSA-69202	Cyclin E associated events during G1/S transition
R-HSA-69205	G1/S-Specific Transcription
R-HSA-69231	Cyclin D associated events in G1
R-HSA-69656	Cyclin A:Cdk2-associated events at S phase entry

MSigDB gene sets: 189 (showing top): RNGTGGGC_UNKNOWN, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_G1_S_SPECIFIC_TRANSCRIPTION, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, chr16q22, CCAWYNNGAAR_UNKNOWN, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_EPITHELIAL_CELL_DEVELOPMENT, AP2_Q3, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_CENTRIOLE_ASSEMBLY, GGAANCGGAANY_UNKNOWN, GOBP_CILIUM_ORGANIZATION, GOBP_REGULATION_OF_CELL_SIZE

GO Biological Process (15): G1/S transition of mitotic cell cycle (GO:0000082), epithelial cell development (GO:0002064), regulation of transcription by RNA polymerase II (GO:0006357), cell volume homeostasis (GO:0006884), blood circulation (GO:0008015), animal organ morphogenesis (GO:0009887), regulation of cell population proliferation (GO:0042127), motile cilium assembly (GO:0044458), positive regulation of transcription by RNA polymerase II (GO:0045944), centriole assembly (GO:0098534), multi-ciliated epithelial cell differentiation (GO:1903251), regulation of DNA-templated transcription (GO:0006355), regulation of cell size (GO:0008361), cell projection organization (GO:0030030), cilium assembly (GO:0060271)

GO Molecular Function (12): 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 (GO:0001216), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein domain specific binding (GO:0019904), protein dimerization activity (GO:0046983), sequence-specific double-stranded DNA binding (GO:1990837), promoter-specific chromatin binding (GO:1990841), chromatin binding (GO:0003682), protein binding (GO:0005515)

GO Cellular Component (6): chromatin (GO:0000785), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), RNA polymerase II transcription regulator complex (GO:0090575), nucleus (GO:0005634), transcription regulator complex (GO:0005667)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
G0 and Early G1	2
G1/S Transition	2
Mitotic G1 phase and G1/S transition	1
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1
TP53 Regulates Transcription of Cell Cycle Genes	1
G1 Phase	1
S Phase	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
cellular anatomical structure	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
positive regulation of DNA-templated transcription	2
DNA-binding transcription factor activity	2
transcription cis-regulatory region binding	2
protein binding	2
binding	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G1/S phase transition	1
epithelial cell differentiation	1
cell development	1
regulation of cell size	1
cellular homeostasis	1
circulatory system process	1
anatomical structure morphogenesis	1
animal organ development	1
cell population proliferation	1
regulation of cellular process	1
cilium assembly	1
microtubule organizing center organization	1
membraneless organelle assembly	1
columnar/cuboidal epithelial cell differentiation	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
regulation of cellular component size	1
cellular component organization	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
cis-regulatory region sequence-specific DNA binding	1

Protein interactions and networks

STRING

2164 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
E2F4	RBL2	Q08999	997
E2F4	SMAD3	P84022	993
E2F4	TFDP1	Q14186	977
E2F4	SMAD4	Q13485	972
E2F4	HDAC1	Q13547	972
E2F4	LIN54	Q6MZP7	943
E2F4	LIN9	Q5TKA1	939
E2F4	SUV39H1	O43463	936
E2F4	MCIDAS	D6RGH6	931
E2F4	E2F5	Q15329	900
E2F4	LIN37	Q96GY3	899
E2F4	SIN3A	Q96ST3	897
E2F4	RB1	P06400	884
E2F4	MYC	P01106	876
E2F4	DNMT1	P26358	857

IntAct

99 interactions, top by confidence:

A	B	Type	Score
CDK2	CCNE2	psi-mi:“MI:0914”(association)	0.940
CDK2	CCNB1	psi-mi:“MI:0914”(association)	0.890
CDKN1A	CCNE2	psi-mi:“MI:0914”(association)	0.890
CDK2	CCNB2	psi-mi:“MI:0914”(association)	0.860
TFDP1	E2F4	psi-mi:“MI:0915”(physical association)	0.810
RBBP4	CDK2AP1	psi-mi:“MI:0914”(association)	0.790
GMNN	MCIDAS	psi-mi:“MI:0914”(association)	0.770
E2F4	TFDP2	psi-mi:“MI:0407”(direct interaction)	0.770
RB1	E2F4	psi-mi:“MI:0915”(physical association)	0.760
E2F4	RB1	psi-mi:“MI:0915”(physical association)	0.760
RBL2	E2F4	psi-mi:“MI:0915”(physical association)	0.750
E2F4	RBL2	psi-mi:“MI:0915”(physical association)	0.750
RB1	TFDP2	psi-mi:“MI:0915”(physical association)	0.740
LIN37	MYBL2	psi-mi:“MI:0914”(association)	0.730
LIN9	MYBL2	psi-mi:“MI:0914”(association)	0.720
E2F4	LIN9	psi-mi:“MI:0915”(physical association)	0.670
CCNA2	GMNN	psi-mi:“MI:0914”(association)	0.640
LIN37	MYBL1	psi-mi:“MI:0914”(association)	0.640
LIN54	MYBL2	psi-mi:“MI:0914”(association)	0.560
PIN1	E2F4	psi-mi:“MI:0915”(physical association)	0.560
E2F4	KAT5	psi-mi:“MI:0915”(physical association)	0.560
TFDP2	E2F4	psi-mi:“MI:0915”(physical association)	0.560
E2F4	E7	psi-mi:“MI:0915”(physical association)	0.560
E2F4	BRAF	psi-mi:“MI:0915”(physical association)	0.550
E2F4	BRAF	psi-mi:“MI:2364”(proximity)	0.550
BRAF	E2F4	psi-mi:“MI:0915”(physical association)	0.550

BioGRID (600): E2F4 (Affinity Capture-RNA), E2F4 (Affinity Capture-RNA), E2F4 (Affinity Capture-RNA), E2F4 (Affinity Capture-Western), E2F4 (Affinity Capture-Western), PML (Affinity Capture-Western), RBL2 (Affinity Capture-Western), E2F4 (Affinity Capture-MS), E2F4 (Affinity Capture-MS), E2F4 (Affinity Capture-MS), E2F4 (Affinity Capture-MS), TFDP1 (Affinity Capture-Western), TFDP2 (Affinity Capture-Western), RBL1 (Affinity Capture-Western), RB1 (Affinity Capture-Western)

ESM2 similar proteins: A2A5K6, F1QQA8, G3V893, O08696, O14901, O57415, P36197, P37275, P97691, Q04891, Q07243, Q08050, Q14872, Q16254, Q2QGD7, Q3UH06, Q5EAC5, Q5F293, Q60542, Q62255, Q62947, Q64318, Q66K89, Q6DBW0, Q6YND2, Q7TS63, Q80X44, Q86V15, Q86VK4, Q8BG87, Q8BKX7, Q8BX22, Q8C8V1, Q8CCE9, Q8IVH2, Q91X45, Q92766, Q96CK0, Q99607, Q9BYN7

Diamond homologs: A0AVK6, A5HWA8, D4A4D7, E1BE02, E1BKK0, F1LMN3, F1QZ88, F6YVB9, F7EA39, O00716, O35261, O54917, O75461, P56931, Q01094, Q08DY6, Q14209, Q15329, Q16254, Q20619, Q27368, Q58FA4, Q5RIX9, Q61501, Q61502, Q62814, Q6DE14, Q6S7F2, Q8LSZ4, Q8R0K9, Q8RWL0, Q90977, Q96AV8, Q9FNY0, Q9FV70, Q9FV71, Q9LFQ9, O09139, O77051

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
E2F4	down-regulates	PPARG	“transcriptional regulation”
E2F4	“down-regulates quantity by repression”	PPARG	“transcriptional regulation”
E2F4	“down-regulates quantity by repression”	BIRC5	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 65 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1	10	113.4×	2e-17
G0 and Early G1	12	99.5×	5e-20
Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)	8	95.8×	4e-13
Polo-like kinase mediated events	7	83.8×	5e-11
Transcription of E2F targets under negative control by DREAM complex	8	82.1×	1e-12
Cyclin E associated events during G1/S transition	14	75.4×	4e-21
TP53 Regulates Transcription of Cell Cycle Genes	7	71.8×	1e-10
Cyclin A:Cdk2-associated events at S phase entry	14	70.2×	7e-21

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of G1/S transition of mitotic cell cycle	6	35.3×	7e-06
G1/S transition of mitotic cell cycle	9	29.6×	1e-08
positive regulation of fibroblast proliferation	6	29.1×	2e-05
regulation of mitotic cell cycle	5	19.7×	5e-04
protein import into nucleus	7	16.5×	4e-05
negative regulation of cell growth	5	11.8×	4e-03
regulation of protein stability	5	10.3×	5e-03
regulation of cell cycle	8	9.8×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1889 predictions. Top by Δscore:

Variant	Effect	Δscore
16:67192330:G:GT	donor_gain	1.0000
16:67192339:G:GT	donor_gain	1.0000
16:67192359:GCTG:G	donor_gain	1.0000
16:67192373:GGC:G	donor_gain	1.0000
16:67192374:GC:G	donor_gain	1.0000
16:67192381:G:T	donor_gain	1.0000
16:67192390:G:GT	donor_gain	1.0000
16:67192391:G:T	donor_gain	1.0000
16:67192652:G:GT	donor_gain	1.0000
16:67192760:GGCA:G	acceptor_gain	1.0000
16:67192822:A:T	donor_gain	1.0000
16:67192867:GGAA:G	donor_gain	1.0000
16:67192868:GAA:G	donor_gain	1.0000
16:67192868:GAAG:G	donor_gain	1.0000
16:67192871:G:GG	donor_gain	1.0000
16:67193154:G:GT	donor_gain	1.0000
16:67193198:G:T	donor_gain	1.0000
16:67194392:TTCTA:T	acceptor_loss	1.0000
16:67194393:TCTAG:T	acceptor_loss	1.0000
16:67194396:A:G	acceptor_loss	1.0000
16:67194681:TCTA:T	acceptor_loss	1.0000
16:67194683:TAG:T	acceptor_loss	1.0000
16:67194684:A:AT	acceptor_loss	1.0000
16:67194684:AG:A	acceptor_gain	1.0000
16:67194685:GG:G	acceptor_gain	1.0000
16:67194884:G:GT	donor_gain	1.0000
16:67195780:A:AG	acceptor_gain	1.0000
16:67195781:G:GG	acceptor_gain	1.0000
16:67195781:GTGA:G	acceptor_gain	1.0000
16:67195839:T:A	acceptor_gain	1.0000

AlphaMissense

2687 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:67192276:C:T	R17W	1.000
16:67192285:A:G	K20E	1.000
16:67192288:A:C	S21R	1.000
16:67192288:A:T	S21C	1.000
16:67192289:G:T	S21I	1.000
16:67192290:C:A	S21R	1.000
16:67192290:C:G	S21R	1.000
16:67192292:T:A	L22Q	1.000
16:67192292:T:C	L22P	1.000
16:67192292:T:G	L22R	1.000
16:67192294:G:A	G23R	1.000
16:67192294:G:C	G23R	1.000
16:67192295:G:A	G23E	1.000
16:67192298:T:C	L24P	1.000
16:67192300:C:T	L25F	1.000
16:67192301:T:A	L25H	1.000
16:67192301:T:C	L25P	1.000
16:67192303:A:C	T26P	1.000
16:67192304:C:A	T26N	1.000
16:67192304:C:T	T26I	1.000
16:67192312:T:A	F29I	1.000
16:67192312:T:C	F29L	1.000
16:67192312:T:G	F29V	1.000
16:67192313:T:C	F29S	1.000
16:67192313:T:G	F29C	1.000
16:67192314:C:A	F29L	1.000
16:67192314:C:G	F29L	1.000
16:67192315:G:A	V30M	1.000
16:67192316:T:A	V30E	1.000
16:67192322:T:C	L32P	1.000

dbSNP variants (sampled 300 via entrez): RS1000042920 (16:67198827 C>T), RS1000155738 (16:67198591 C>T), RS1000421645 (16:67192500 G>A,C), RS1000495378 (16:67197142 T>G), RS1000694177 (16:67194487 T>A,G), RS1001044535 (16:67197547 G>A), RS1001271906 (16:67192639 C>T), RS1001325794 (16:67192445 T>A), RS1001480494 (16:67198459 C>A,G,T), RS1001744347 (16:67198733 C>T), RS1002042663 (16:67197528 A>G), RS1002312187 (16:67192088 A>G,T), RS1003168552 (16:67197286 G>A), RS1003867702 (16:67192251 G>C), RS1003918281 (16:67192439 C>A,T)

Disease associations

OMIM: gene MIM:600659 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST90002390_89	Mean corpuscular hemoglobin	2.000000e-12
GCST90002392_505	Mean corpuscular volume	1.000000e-15
GCST90002396_588	Mean reticulocyte volume	4.000000e-10
GCST90002396_589	Mean reticulocyte volume	8.000000e-15
GCST90002397_240	Mean spheric corpuscular volume	5.000000e-14
GCST90002397_241	Mean spheric corpuscular volume	5.000000e-27

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630726 (PROTEIN FAMILY)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
Valproic Acid	affects expression, decreases expression, increases expression, increases methylation	4
Arsenic Trioxide	increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Estradiol	affects expression, increases expression	2
Fluorouracil	affects binding, affects reaction, increases reaction, decreases expression	2
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
juglone	decreases reaction, increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
afimoxifene	increases expression, decreases reaction	1
cypermethrin	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	affects expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
coptisine	affects binding, decreases reaction, decreases expression	1
cylindrospermopsin	increases expression	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases expression	1
ICG 001	increases expression	1
Rosiglitazone	decreases expression	1
Sunitinib	increases expression	1
Glyphosate	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	1
Cadmium	increases abundance, increases expression	1
Caffeine	increases phosphorylation	1
Chelating Agents	affects binding, decreases expression	1
Copper	affects binding, decreases expression	1
Diazinon	decreases methylation	1
Dibutyl Phthalate	increases expression	1
Doxorubicin	decreases expression	1

Cellosaurus cell lines

7 cell lines: 3 embryonic stem cell, 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A1C4	SEES3-1V human E2F4, clone1	Embryonic stem cell	Male
CVCL_A1C5	SEES3-1V human E2F4, clone2	Embryonic stem cell	Male
CVCL_A1C6	SEES3-1V human E2F4, clone3	Embryonic stem cell	Male
CVCL_B2W6	Abcam HEK293T E2F4 KO	Transformed cell line	Female
CVCL_D8KK	Ubigene HCT 116 E2F4 KO	Cancer cell line	Male
CVCL_GZ79	K562 eGFP-E2F4	Cancer cell line	Female
CVCL_HA12	MCF-7 eGFP-E2F4	Cancer cell line	Female

Clinical trials (associated diseases)

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