Alternative titles; symbols
HGNC Approved Gene Symbol: ELF2
Cytogenetic location: 4q31.1 Genomic coordinates (GRCh38) : 4:139,057,220-139,177,915 (from NCBI)
ELF2 is widely expressed in hemopoietic tissues and transcriptionally regulates genes involved in early B- and T-cell development (Guan et al., 2017).
By database analysis and 5-prime RACE using human spleen and fetal liver cDNA libraries, Oettgen et al. (1996) cloned 3 splice variants of ELF2, which they named NERF. The 3 variants, NERF1a, NERF1b, and NERF2, differ only at their 5-prime ends. NERF1a encodes a predicted 521-amino acid protein with a calculated molecular mass of 56.1 kD. NERF1b encodes a predicted 533-amino acid protein with a calculated molecular mass of 57.4 kD and has a 12-amino acid insertion relative to NERF1a. NERF2 encodes a 581-amino acid protein with a calculated molecular mass of 62.7 kD and has a unique N terminus compared with NERF1a and NERF1b. All 3 NERF isoforms have an N-terminal acidic domain, followed by a basic domain, an ETS DNA-binding domain, and a serine-rich domain, as well as several potential phosphorylation sites. Among members of the ETS family, NERF shares highest amino acid homology with ELF1 (189973), especially within the ETS domain. Northern blot analysis detected variable expression of 2.9- and 3.2-kb NERF transcripts in all human fetal and adult tissues tested.
Wilkinson et al. (1997) cloned 2 splice variants of mouse Elf2 that they designated Elf2a and Elf2b. The Elf2a and Elf2b isoforms contain 581 and 521 amino acids, respectively, and both have DNA-binding motifs and a C-terminal Rbtn2 (LMO2; 180385)-binding domain. Elf2a also has a putative transactivation domain that is absent in Elf2b. Northern blot analysis detected 2 Elf2 transcripts expressed at similar levels in all mouse tissues tested except thymus. Thymocytes expressed 4- to 10-fold more Elf2b than Elf2a. In addition, Northern blot analysis showed similar levels of 2 ELF2 transcripts in human hematopoietic cell lines, with higher expression of ELF2B than ELF2A in thymocytes.
Using quantitative RT-PCR analysis, Guan et al. (2017) showed that Elf2 variants were expressed at similar levels in mouse brain, heart, kidney, liver, and lung. However, Elf2b was preferentially expressed in thymus and spleen, and Elf2a was preferentially expressed in testis. Western blot analysis confirmed a similar differential expression pattern of Elf2 isoforms in mouse tissues and cells. Bioinformatic analysis suggested that the ELF2 isoforms may autoregulate their own expression. Elf2 isoforms predominantly localized to nuclei in mouse CH12 and A20 B-lymphoma cell lines.
Guan et al. (2017) reported that the ELF2 gene contains at least 10 exons.
Guan et al. (2017) stated that the ELF2 gene maps to chromosome 4q13.1.
Using an in vitro binding assay, Oettgen et al. (1996) showed that NERF interacted specifically with ETS-related binding sites in various genes through its DNA-binding domain. All 3 NERF isoforms exhibited comparable affinity for ETS-related binding sites. However, NERF2 acted as a transactivator, whereas NERF1a and NERF1b did not. Further analysis identified the promoter regions of the human LYN (165120) and mouse Blk (191305) genes as potential B-cell targets for NERF2.
By yeast 2-hybrid screening, Wilkinson et al. (1997) showed that mouse Elf2 bound to Rbtn2. Both LIM domains of Rbtn2 were necessary and sufficient for binding Elf2.
Using a chromatin immunoprecipitation assay, Zhang et al. (2007) showed that ELF2 bound specifically to the 5-prime-flanking sequence of the VCP gene (601023) in MCF7 human breast cancer cells. Knockdown of ELF2 in MCF7 cells reduced VCP expression and cell viability. Immunohistochemical analysis revealed that ELF2 expression correlated with VCP expression and proliferative activity of cells in breast cancer specimens.
Fausther et al. (2017) identified Elf2 as a transcription factor that negatively regulated expression of Nt5e (129190) in activated mouse liver myofibroblasts during hepatic fibrosis.
By analyzing RNA sequencing data, Guan et al. (2017) found that ELF2 was more highly expressed in acute myeloid leukemia (AML; 601626) than other cancers. Overexpression of ELF2B significantly reduced cellular proliferation in human primary and immortalized cells, as ELF2B overexpression delayed cell cycle progression and induced apoptosis through its N terminus. In vivo analysis with retrogenic mice transplanted with hemopoietic progenitor cells overexpressing Elf2a or Elf2b suggested that the main role of Elf2 was restricted to early development of B and T cells and that compensatory mechanisms existed. No differences in B- and T-cell development were observed between the ELF2 isoforms.
Associations Pending Confirmation
For discussion of a possible association between an autosomal dominant form of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; see 614575) and variation in the ELF2 gene, see 619798.0001.
This variant is classified as a variant of unknown significance because its contribution to autosomal dominant cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; see 614575) has not been confirmed.
In 3 members of a British family with a clinical diagnosis of autosomal dominant CANVAS, Ahmad et al. (2018) identified a heterozygous c.10G-A transition (c.10G-A, NM_201999.2) in exon 2 of the ELF2 gene, resulting in an ala4-to-thr (A4T) substitution in a conserved region of the N terminus. The variant, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. In vitro functional expression studies in a human neuroblastoma cell line transfected with the mutation showed increased expression of ELF2 and ATXN2 (601517) and decreased expression of ELOVL5 (611805). Mutations in ATXN2 and ELOVL5 are associated with SCA2 (183090) and SCA38 (615957), respectively. Confocal microscopy confirmed the cytoplasmic overexpression of ATXN2. Mutant cells showed reduced numbers of smaller lipid droplets compared to wildtype. These findings suggested that the ELF2 transcription factor may regulate other proteins involved in hereditary ataxias. The patients had onset of symptoms between 58 and 72 years of age. They had slowly progressive distal sensory loss with ataxic gait, impaired balance, positive Romberg test, and absent ankle jerks. Other features included dysarthria, dysphagia, cough, lower limb dysmetria, oscillopsia, nystagmus, and hypometric saccades. One patient had difficulties with micturition and erectile dysfunction. Electrophysiologic studies showed an axonal sensory neuronopathy and bilateral absence of vestibular function. Brain imaging showed cerebellar atrophy in 2 patients and mild global atrophy in the third. Cervical spine imaging in 1 patient was compatible with dorsal root ganglionopathy. Autonomic function was normal. The transmission pattern of the neurologic phenotype in this family was consistent with autosomal dominant inheritance with incomplete penetrance and variable expressivity.
Ahmad, H., Requena, T., Frejo, L., Cobo, M., Gallego-Martinez, A., Martin, F., Lopez-Escamez, J. A., Bronstein, A. M. Clinical and functional characterization of a missense ELF2 variant in a CANVAS family. Front. Genet. 9: 85, 2018. [PubMed: 29628936] [Full Text: https://doi.org/10.3389/fgene.2018.00085]
Fausther, M., Lavoie, E. G., Goree, J. R., Dranoff, J. A. An Elf2-like transcription factor acts as a repressor of the mouse ecto-5-prime-nucleotidase gene expression in hepatic myofibroblasts. Purinergic Signal. 13: 417-428, 2017. [PubMed: 28667437] [Full Text: https://doi.org/10.1007/s11302-017-9570-7]
Guan, F. H. X., Bailey, C. G., Metierre, C., O'Young, P., Gao, D., Khoo, T. L., Holst, J., Rasko, J. E. J. The antiproliferative ELF2 isoform, ELF2B, induces apoptosis in vitro and perturbs early lymphocytic development in vivo. J. Hematol. Oncol. 10: 75, 2017. [PubMed: 28351373] [Full Text: https://doi.org/10.1186/s13045-017-0446-7]
Oettgen, P., Akbarali, Y., Boltax, J., Best, J., Kunsch, C., Libermann, T. A. Characterization of NERF, a novel transcription factor related to the Ets factor ELF-1. Molec. Cell. Biol. 16: 5091-5106, 1996. [PubMed: 8756667] [Full Text: https://doi.org/10.1128/MCB.16.9.5091]
Wilkinson, D. A., Neale, G. A. M., Mao, S., Naeve, C. W., Goorha, R. M. Elf-2, a rhombotin-2 binding ets transcription factor: discovery and potential role in T cell leukemia. Leukemia 11: 86-96, 1997. [PubMed: 9001422] [Full Text: https://doi.org/10.1038/sj.leu.2400516]
Zhang, B., Tomita, Y., Qiu, Y., He, J., Morii, E., Noguchi, S., Aozasa, K. E74-like factor 2 regulates vasolin-containing protein expression. Biochem. Biophys. Res. Commun. 356: 536-541, 2007. [PubMed: 17368566] [Full Text: https://doi.org/10.1016/j.bbrc.2007.02.160]