ELF4 (E74-like factor 4 (ets domain transcription factor))

2013-12-01   Stephen D Nimer , Yan Liu 

Sylvester Comprehensive Cancer Center Professor of Medicine, Biochemistry & Molecular Biology, University of Miami, USA (SDN); Indiana University School of Medicine, USA (YL)




Atlas Image
The ELF4 gene is located on the X-chromosome (Xq26) and is transcribed from telomere to centromere. The ELF4 gene contains 8 coding exons and 1 non-coding exon.


The gene encompasses 45 kb of DNA; 9 exons. The ELF4 gene contains 12 distinct gt-ag introns. Transcription produces 5 alternatively spliced mRNAs. There are 2 probable alternative promoters, 2 non overlapping alternative last exons and 2 validated alternative polyadenylation sites. The mRNAs appear to differ by truncation of the 3 end, presence or absence of 3 cassette exons, overlapping exons with different boundaries, splicing versus retention of 2 introns.


4190 bp mRNA; 1991 bp open reading frame.


No observed pseudogenes.


Atlas Image
The ELF4 protein contains the following domains: (A) transactivation domain, (B) AML1 interacting domain, (C) ETS domain, (D) serine/threonine rich region and (E) proline rich region.


663 amino acids; 70730 Da protein; numerous posttranslational modifications: phosphorylation, sumoylation and ubiquitination (Miyazaki et al., 2001; Liu et al., 2006; Suico et al., 2006). ELF4 contains, from N-term to C-term, transactivation domain (53-86), AML1 interacting domain (87-206), ETS domain (207-291), serine/threonine rich region (306-347) and proline rich region (477-517) (Miyazaki et al., 1996; Mao et al., 1999; Suico et al., 2002; Lacorazza and Nimer, 2003).


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 (Lacorazza and Nimer, 2003).


Nucleus, PML body. Accumulation into PML nuclear bodies is mediated by PML (Suico et al., 2004a; Suico et al., 2004b).


ELF4 is a member of the ETS family of transcription factors (TF) with transcription activating properties (Lacorazza and Nimer, 2003). ELF4 binds to DNA sequences containing the consensus 5-WGGA-3 and transactivates promoters of the hematopoietic growth factor genes CSF2, IL3, IL8, and of the bovine lysozyme gene (Miyazaki et al., 1996; Mao et al., 1999; Hedvat et al., 2004; Suico et al., 2004). ELF4 acts synergistically with RUNX1 to transactivate the IL3 promoter (Mao et al., 1999). It also transactivates the PRF1 promoter in natural killer (NK) cells (Lacorazza et al., 2002). ELF4 has important molecular functions, including protein binding, transcription activator activity, sequence-specific DNA binding, transcription factor activity. ELF4 interacts with multiple proteins, including Cyclin A/CDK2 kinase complex, FBXO4, FBXO7, PML, RUNX1, SKP2 and UBB (Miyazaki et al., 1996; Mao et al., 1999; Miyazaki et al., 2001; Liu et al., 2006; Suico et al., 2006). ELF4 has been implicated in widely divergent physiological and pathological processes (such as development and oncogenesis). ELF4 plays an important role in the development and function of NK and NK T-cells and in innate immunity (Lacorazza et al., 2002). It controls the proliferation and homing of CD8+ T-cells via the Kruppel-like factors KLF4 and KLF2 (Yamada et al., 2009; Yamada et al., 2010). ELF4 regulates hematopoietic stem cell quiescence and self-renewal (Lacorazza et al., 2006; Liu et al., 2009). ELF4 also regulates self-renewal of brain-tumor stem cells (Bazzoli et al., 2012). In addition, ELF4 plays an important role in osteogenic differentiation and bone development (Kim et al., 2007; Seul et al., 2011; Baek et al., 2012). It mediates DNA damage response (Morales et al., 2008; Sashida et al., 2011). ELF4 controls cell senescence in a p53-dependent manner and can also promote cellular transformation through inhibition of the p16 pathway as well (Sashida et al., 2009). ELF4, a member of the ETS transcription factors, can function as an oncogene in murine cancer models and is overexpressed in various human cancers (Lacorazza and Nimer, 2003; Sashida et al., 2010). In addition to its oncogenic potential, ELF4 has been proposed to be a candidate tumor suppressor gene on the X chromosome (Seki et al., 2002).
Atlas Image
ELF4 interacts with multiple proteins and plays important role in development and oncogenesis.


The transcription factor ELF4 belongs to the ETS family of transcription factors, named after the E26 (E twenty six) leukemogenic chicken virus which contains a gag-myb-ets fusion. These proteins are characterized by the presence of the ETS domain (a conserved 84 amino acid domain) that binds to a DNA consensus sequence containing a GGAA central core via a winged helix-turn-helix motif. Based on the homology of the ETS domain, these proteins have been classified in different subfamilies (e.g., Elf, Spi, and Yan). The ETS domain is highly conserved among family members with the greatest homology of ELF4 with other proteins in the Elf subfamily, which also includes ELF1, NERF1a, and NERF1b. ELF4 does not contain an HLH or pointed protein-protein interaction domain, which is present in members of the ETS, ERG, GABP, and Yan subfamilies (Lacorazza and Nimer, 2003).



No known mutations. Fused in hepatocellular carcinoma with the BCORL1 gene.

Implicated in

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. It usually occurs around age 60 with no identifiable cause and it carries a very poor prognosis, with most patients living less than 18 months. AML is a devastating illness with over 13000 new diagnoses and 10000 patients dying annually in the United States. Although select molecular subpopulations of patients are long-term survivors, the overall five-year survival for adults is only 25%. ETS proteins (such as PU.1, Fli-1 and ETS-1) have been shown to play important roles in normal and abnormal hematopoiesis (Lacorazza and Nimer, 2003). ELF1 and ELF4 were expressed in all AML samples, whereas NERF was not. The relative expression of ELF4, but not ELF1, was significantly lower (P
The low relative expression of ELF4, might be part of a gene expression profile characterizing AML with a good prognosis (Fukushima et al., 2003; Ando et al., 2013).
A chromosomal translocation has been reported in AML, t(X;21)(q25-26;q22), that generates a fusion transcript between two ETS family members, ELF4 (at Xq26) and ERG (at 21q22). The translocation occurs within intron 1 of ERG isoform 1 (ERG-1) and intron 2 of ELF4 resulting in an in-frame fusion joining exon 2 from ELF4 with exon 2 of ERG (Moore et al., 2006).
Hybrid gene
ELF4-ERG. The fusion sequence includes exon 2 of ELF4 and exon 2 of ERG1, with the breakpoint occurring after exon 2 in ELF4 (intron 2) and before exon 2 of ERG1 (intron 1) (Moore et al., 2006).
Fusion protein
ELF4-ERG (495 amino acids).
Atlas Image
Horizontal lines represent amino acid residues for ELF4 and ERG-1. Numbers above each line indicate the number of amino acids at the corresponding position. Boxes below indicate locations of the conserved domains within both protein sequences. The predicted fusion protein would include the first 25 amino acid residues from ELF4 encoded by exon 2 and the last 470 amino acid residues encoded by ERG exons 2-10 resulting in a protein of 495 amino acids. The conserved SAM-PNT and ETS domains from ERG would be included in the fusion while the ETS domain from ELF4 would be excluded.
ERG has been associated with other fusion partners, specifically FUS and EWSR1, and implicated in both AML and Ewings sarcoma. The ELF4-ERG fusion suggests a new role for ELF4 in leukemogenesis and human cancer (Moore et al., 2006), as it provides a strong promoter to express ERG. In addition, wild-type nucleophosmin (NPM1) inhibits the DNA binding and transcriptional activity of ELF4 on the HDM2 promoter, while a common, leukemia-associated NPM1 mutant protein (Mt-NPM1) enhances these activities of ELF4 (Ando et al., 2013). Moreover, clinical leukemia samples with NPM1 mutations have higher human MDM2 (HDM2) mRNA expression. These data suggest that enhanced HDM2 expression induced by mutant NPM1 may have a role in ELF4-dependent leukemogenesis (Ando et al., 2013).
Entity name
Ovarian cancer
Ovarian cancer is the seventh most common cancer in women worldwide and the second leading cause of death among the gynecological malignancies. ELF4 is expressed in a significant proportion of ovarian carcinomas, and in the CAOV3 and SKOV3 ovarian cancer cell lines, but not in normal ovarian surface epithelium (Yao et al., 2007).
High levels of ELF4 expression in ovarian cancer are associated with a poor prognosis (Yao et al., 2007).
Manipulating MEF levels in ovarian cancer cell lines alters their behavior; reducing ELF4 levels, using short hairpin RNA expressing vectors, significantly inhibited the proliferation of SKOV3 and CAOV3 cells in culture, and impaired the anchorage-independent growth of CAOV3 cells. Overexpression of ELF4 in SKOV3 cells significantly increased their growth rate, enhanced colony formation in soft agar and promoted tumor formation in nude mice. The oncogenic activity of MEF was further shown by the ability of ELF4 to transform NIH3T3 cells, and induce their tumor formation in nude mice (Yao et al., 2007). Thus, ELF4 is an important regulator of the tumorigenic properties of ovarian cancer cells and could be used a therapeutic target in ovarian cancer (Yao et al., 2007).
Entity name
Malignant gliomas represent the most prevalent primary brain tumor in adults and inevitably have a poor prognosis. Despite the implementation of new therapeutic strategies, the median survival of patients with glioblastoma multiforme (GBM), the most aggressive glioma variant, is only 14-16 months and these tumors remain rapidly and uniformly fatal. High-grade gliomas are composed of a heterogeneous population of cells that include many with stem-cell-like properties. The acquisition of stem-like traits might contribute to glioma initiation, growth, and recurrence. ELF4 is highly expressed in both human and mouse glioblastomas and its absence impairs gliomagenesis in a PDGF-driven glioma mouse model (Bazzoli et al., 2012).
High levels of ELF4 expression in gliomas are associated with a poor prognosis (Bazzoli et al., 2012).
Modulation of ELF4 levels in both mouse neural stem cells and human glioblastoma cells has a significant impact on neurosphere formation. Thus, ELF4 is a gatekeeper gene that promotes stemness in the pathogenesis of gliomas (Bazzoli et al., 2012).


Pubmed IDLast YearTitleAuthors
233931362013Mutations in the nucleolar phosphoprotein, nucleophosmin, promote the expression of the oncogenic transcription factor MEF/ELF4 in leukemia cells and potentiates transformation.Ando K et al
223075232012Myeloid Elf-1-like factor stimulates adipogenic differentiation through the induction of peroxisome proliferator-activated receptor γ expression in bone marrow.Baek K et al
232174242012MEF promotes stemness in the pathogenesis of gliomas.Bazzoli E et al
126202892003The level of MEF but not ELF-1 correlates with FAB subtype of acute myeloid leukemia and is low in good prognosis cases.Fukushima T et al
146253022004Myeloid ELF1-like factor is a potent activator of interleukin-8 expression in hematopoietic cells.Hedvat CV et al
171677702007The suppressive effect of myeloid Elf-1-like factor (MEF) in osteogenic differentiation.Kim YJ et al
165307022006The transcription factor MEF/ELF4 regulates the quiescence of primitive hematopoietic cells.Lacorazza HD et al
191287912009p53 regulates hematopoietic stem cell quiescence.Liu Y et al
165817862006The ETS protein MEF is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCFSkp2.Liu Y et al
102070871999Functional and physical interactions between AML1 proteins and an ETS protein, MEF: implications for the pathogenesis of t(8;21)-positive leukemias.Mao S et al
115047162001Cyclin A-dependent phosphorylation of the ETS-related protein, MEF, restricts its activity to the G1 phase of the cell cycle.Miyazaki Y et al
163031802006ELF4 is fused to ERG in a case of acute myeloid leukemia with a t(X;21)(q25-26;q22).Moore SD et al
183814242008DNA damage signaling in hematopoietic cells: a role for Mre11 complex repair of topoisomerase lesions.Morales M et al
216169372011The mef/elf4 transcription factor fine tunes the DNA damage response.Sashida G et al
193804902009ELF4/MEF activates MDM2 expression and blocks oncogene-induced p16 activation to promote transformation.Sashida G et al
124382532002The ETS transcription factor MEF is a candidate tumor suppressor gene on the X chromosome.Seki Y et al
207151872011Osteoblast-specific expression of MEF induces osteopenia through downregulation of osteoblastogenesis and upregulation of osteoclastogenesis.Seul KJ et al
121511022002Functional dissection of the ETS transcription factor MEF.Suico MA et al
152864312004The regulation of human beta-defensin 2 by the ETS transcription factor MEF (myeloid Elf-1-like factor) is enhanced by promyelocytic leukemia protein.Suico MA et al
169046442006SUMO down-regulates the activity of Elf4/myeloid Elf-1-like factor.Suico MA et al
149761842004Myeloid Elf-1-like factor, an ETS transcription factor, up-regulates lysozyme transcription in epithelial cells through interaction with promyelocytic leukemia protein.Suico MA et al
208021522010Cutting edge: Expression of the transcription factor E74-like factor 4 is regulated by the mammalian target of rapamycin pathway in CD8+ T cells.Yamada T et al
194121822009Transcription factor ELF4 controls the proliferation and homing of CD8+ T cells via the Krüppel-like factors KLF4 and KLF2.Yamada T et al
172138152007Tumor promoting properties of the ETS protein MEF in ovarian cancer.Yao JJ et al

Other Information

Locus ID:

NCBI: 2000
MIM: 300775
HGNC: 3319
Ensembl: ENSG00000102034


dbSNP: 2000
ClinVar: 2000
TCGA: ENSG00000102034


Gene IDTranscript IDUniprot

Expression (GTEx)


Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
146253022004Myeloid ELF1-like factor is a potent activator of interleukin-8 expression in hematopoietic cells.16
232174242012MEF promotes stemness in the pathogenesis of gliomas.14
159074862005Sp1-dependent regulation of Myeloid Elf-1 like factor in human epithelial cells.11
150137612004MEF up-regulates human beta-defensin 2 expression in epithelial cells.10
163031802006ELF4 is fused to ERG in a case of acute myeloid leukemia with a t(X;21)(q25-26;q22).8
250815432014The transcription factor MEF/Elf4 is dually modulated by p53-MDM2 axis and MEF-MDM2 autoregulatory mechanism.7
149761842004Myeloid Elf-1-like factor, an ETS transcription factor, up-regulates lysozyme transcription in epithelial cells through interaction with promyelocytic leukemia protein.6
121511022002Functional dissection of the ETS transcription factor MEF.5
254820122015The transcriptional regulator BCL6 participates in the secondary gene regulatory response to vitamin D.5
213501942011The transcription factor E74-like factor controls quiescence of endothelial cells and their resistance to myeloablative treatments in bone marrow.3


Stephen D Nimer ; Yan Liu

ELF4 (E74-like factor 4 (ets domain transcription factor))

Atlas Genet Cytogenet Oncol Haematol. 2013-12-01

Online version: http://atlasgeneticsoncology.org/gene/42990/elf4