GSE124843
Integrative transcriptomic analysis reveals mechanisms controlling the reciprocity of epithelial and mesenchymal genes during epithelial-to-mesenchymal transition
Epithelial-to-mesenchymal transition (EMT) is an important developmental process that is also activated during disease progressions. Many genes involved in EMT have been identified to date, but the key molecules governing the coupling between the dynamics of epithelial genes and that of the mesenchymal genes are unclear. In addition, it has been shown that there is a remarkable diversity of EMT phenotypes in different pathological conditions or microenvironments, but its mechanistic basis remains elusive. In this study, we used transcriptomic analysis to identify the roles of an EMT-inducing transcription factor ZEB1 in controlling epithelial and mesenchymal genes. We found that the mesenchymal genes exhibit a significant diversity in terms of their responsiveness to ZEB1. We applied machine learning approaches to the transcriptome data and identified three groups of M-genes that are controlled by EMT promoting factors via different types of regulatory circuits. We inferred the functional differences among the M-gene clusters in motility regulation of cultured cells and in survival of breast cancer patients. We characterized the roles of ZEB1 in controlling the reciprocity and reversibility of EMT using mathematical modeling. Our integrative analysis reveals the key roles of ZEB1 in coordinating the dynamics of a large number of genes during EMT, and it provides new insights into the mechanisms for the diversity of EMT phenotypes. Overall design: MCF10A cells were treated by combinations of perturbations as follows: recombinant TGF-beta (200 nM) for 4 weeks, CRISPR/Cas9-mediated ZEB1 knockout, doxycycline-inducible expression of exogenous ZEB1, and TGF-beta type1 receptor inhibiotr (SB-431542, 10microM) treatment