Abstract
BackgroundELF2 (E74-like factor 2) also known as NERF (new Ets-related factor), a member of the Ets family of transcription factors, regulates genes important in B and T cell development, cell cycle progression, and angiogenesis. Conserved ELF2 isoforms, ELF2A, and ELF2B, arising from alternative promoter usage can exert opposing effects on target gene expression. ELF2A activates, whilst ELF2B represses, gene expression, and the balance of expression between these isoforms may be important in maintaining normal cellular function.MethodsWe compared the function of ELF2 isoforms ELF2A and ELF2B with other ELF subfamily proteins ELF1 and ELF4 in primary and cancer cell lines using proliferation, colony-forming, cell cycle, and apoptosis assays. We further examined the role of ELF2 isoforms in haemopoietic development using a Rag1-/-murine bone marrow reconstitution model.ResultsELF2B overexpression significantly reduced cell proliferation and clonogenic capacity, minimally disrupted cell cycle kinetics, and induced apoptosis. In contrast, ELF2A overexpression only marginally reduced clonogenic capacity with little effect on proliferation, cell cycle progression, or apoptosis. Deletion of the N-terminal 19 amino acids unique to ELF2B abrogated the antiproliferative and proapoptotic functions of ELF2B thereby confirming its crucial role. Mice expressing Elf2a or Elf2b in haemopoietic cells variously displayed perturbations in the pre-B cell stage and multiple stages of T cell development. Mature B cells, T cells, and myeloid cells in steady state were unaffected, suggesting that the main role of ELF2 is restricted to the early development of B and T cells and that compensatory mechanisms exist. No differences in B and T cell development were observed between ELF2 isoforms.ConclusionsWe conclude that ELF2 isoforms are important regulators of cellular proliferation, cell cycle progression, and apoptosis. In respect to this, ELF2B acts in a dominant negative fashion compared to ELF2A and as a putative tumour suppressor gene. Given that these cellular processes are critical during haemopoiesis, we propose that the regulatory interplay between ELF2 isoforms contributes substantially to early B and T cell development.
Highlights
ELF2 (E74-like factor 2) known as NERF, a member of the Ets family of transcription factors, regulates genes important in B and T cell development, cell cycle progression, and angiogenesis
ELF2 isoform expression arises from distinct alternative promoter usage: ELF2A expression is driven by promoter P1 or promoter P2, but contains identical coding exons; whereas ELF2B transcription initiates at promoter P3 (Fig. 1a)
Many have been experimentally verified in chromatin immunoprecipitation (ChIP) studies and were identified in putative conserved enhancer regions (+0.5, +1.5, and +8.2) proximal to P3 (ELF2B) (Fig. 1a)
Summary
ELF2 (E74-like factor 2) known as NERF (new Ets-related factor), a member of the Ets family of transcription factors, regulates genes important in B and T cell development, cell cycle progression, and angiogenesis. Conserved ELF2 isoforms, ELF2A, and ELF2B, arising from alternative promoter usage can exert opposing effects on target gene expression. The Ets (E-twenty-six) family of transcription factors, characterised by the presence of an evolutionarily conserved 85 amino acid (aa) Ets DNA-binding domain, utilises a range of factors to govern target specificity. 27 members of the Ets family have been characterised, and many function as critical mediators of a wide variety of cellular processes, which include embryonic development, differentiation, growth, apoptosis, and oncogenic transformation [1,2,3]. Subtle differences in Ets sites, tissue-specific expression of Ets factors and their co-factors, and differential signalling responses may all contribute to their distinct functions, but makes identifying true targets both problematic and challenging [8, 9]
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