Abstract
Epithelial-to-mesenchymal transition (EMT), a fundamental transdifferentiation process in development, produces diverse phenotypes in different physiological or pathological conditions. Many genes involved in EMT have been identified to date, but mechanisms contributing to the phenotypic diversity and those governing the coupling between the dynamics of epithelial (E) genes and that of the mesenchymal (M) genes are unclear. In this study, we employed combinatorial perturbations to mammary epithelial cells to induce a series of EMT phenotypes by manipulating two essential EMT-inducing elements, namely TGF-β and ZEB1. By measuring transcriptional changes in more than 700 E-genes and M-genes, we discovered that the M-genes exhibit a significant diversity in their dependency to these regulatory elements and identified three groups of M-genes that are controlled by different regulatory circuits. Notably, functional differences were detected among the M-gene clusters in motility regulation and in survival of breast cancer patients. We computationally predicted and experimentally confirmed that the reciprocity and reversibility of EMT are jointly regulated by ZEB1. 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.
Highlights
In epithelial-to-mesenchymal transition (EMT), a developmental program essential for morphogenic processes in embryogenesis and crucial in pathogenesis of malignant tumors, the cell-state transition occurs between two major states, epithelial (E) and mesenchymal (M), with well-characterized morphological features.[1,2,3] In the classical EMT process during development, transition from E to M state is unidirectional and two phenotypes are mutually exclusive
This diversity may be attributed to the metastable states that exist between terminal E and M states.[2,4,5,6]
We identified the key roles of ZEB1 in regulations of the coupling between E-genes and M-genes
Summary
In epithelial-to-mesenchymal transition (EMT), a developmental program essential for morphogenic processes in embryogenesis and crucial in pathogenesis of malignant tumors, the cell-state transition occurs between two major states, epithelial (E) and mesenchymal (M), with well-characterized morphological features.[1,2,3] In the classical EMT process during development, transition from E to M state is unidirectional and two phenotypes are mutually exclusive. TGF-β failed to downregulate E-cad in KO cells, while VIM was still upregulated to the similar extent with the WT cells (Supplementary Fig. 2) These results suggest that while ZEB1 is a potent EMT-inducing transcription factor, its expression is dispensable for the induction of some M-genes. Treatment with TGF-β inhibitor upon withdrawal of exogenous ZEB1 expression caused a partial reversal of the EMT (Fig. 6g, bottom panel, Fig. 6h, right panel) These results suggest that the endogenous ZEB1 with its feedback regulation is essential for maintenance of irreversible EMT phenotype in mammary epithelial cells as reported for other cell types.[30] Together with the results shown in earlier sections, our data indicate that the irreversibility and the reciprocity of EMT are both regulated by ZEB1, and these two properties may be closely related
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