Cooperative RNA degradation stabilizes intermediate epithelial-mesenchymal states and supports a phenotypic continuum.

Multiple intermediate epithelial-mesenchymal transition (EMT) states reflecting hybrid epithelial and mesenchymal phenotypes were observed in physiological and pathological conditions. Previous theoretical models explaining multiple EMT states rely on regulatory loops involving transcriptional feedback, which produce three or four attractors. This is incompatible with the observed continuum-like EMT spectrum. Here, we used mass-action-based models to describe post-transcriptional regulations, finding that cooperative RNA degradation via multiple microRNA binding sites can generate four-attractor systems without transcriptional feedback. Furthermore, the newly identified intermediates-enabling circuits are common in the EMT regulatory network, and they can synergize with transcriptional feedback to support phenotypic continuum. Finally, our model predicted a role of miR-101 in multistate EMT, and we identified evidence from single-cell RNA-sequencing data that support the prediction. Our work reveals a previously unknown role of cooperative RNA degradation and microRNAs in EMT, providing a framework that can bridge the gap between mechanistic models and single-cell experiments.