The ELF3 transcription factor is associated with an epithelial phenotype and represses epithelial-mesenchymal transition

Abstract

Abstract Background Epithelial-mesenchymal plasticity (EMP) involves bidirectional transitions between epithelial, mesenchymal and multiple intermediary hybrid epithelial/mesenchymal phenotypes. While the process of epithelial-mesenchymal transition (EMT) and its associated transcription factors are well-characterised, the transcription factors that promote mesenchymal-epithelial transition (MET) and stabilise hybrid E/M phenotypes are less well understood. Results Here, we analyse multiple publicly-available transcriptomic datasets at bulk and single-cell level and pinpoint ELF3 as a factor that is strongly associated with an epithelial phenotype and is inhibited during EMT. Using mechanism-based mathematical modelling, we also show that ELF3 inhibits the progression of EMT. This behaviour was also observed in the presence of an EMT inducing factor WT1. Our model predicts that the MET induction capacity of ELF3 is stronger than that of KLF4, but weaker than that of GRHL2. Finally, we show that ELF3 levels correlates with worse patient survival in a subset of solid tumour types. Conclusion ELF3 is shown to be inhibited during EMT progression and is also found to inhibit the progression of complete EMT suggesting that ELF3 may be able to counteract EMT induction, including in the presence of EMT-inducing factors, such as WT1. The analysis of patient survival data indicates that the prognostic capacity of ELF3 is specific to cell-of-origin or lineage.

Keywords

• ELF3
• Phenotypic plasticity
• Mathematical modelling
• Epithelial-mesenchymal transition (EMT)
• Mesenchymal
• Epithelial Transition (MET)