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.

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).

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.