Network Edge Editing Reveals the Control Architecture of EMT

Epithelial–mesenchymal plasticity emerges from a dense regulatory architecture of transcription factors and microRNAs whose interactions, rather than the nodes themselves, dictate phenotypic state. To probe, understand, and potentially control this architecture, we engineered a suite of CRISPR/Cas9 "edgetic" perturbations that selectively delete, redirect, or create miRNA–TF interactions within the EMT network. Disrupting the miR-22/Snai1 edge revealed unexpected global shifts in mesenchymal programs, while CRISPR-HDR–mediated edge creation enabled EMT-responsive miRNAs to be co-opted as synthetic control inputs capable of biasing or even immunizing cells against EMT progression. Together, these approaches expose the hierarchical logic embedded in miRNA–TF wiring and demonstrate that EMT trajectories can be predictably steered by reprogramming edges, not nodes. This work introduces a generalizable framework for decoding and rewriting regulatory networks and highlights new intervention points for controlling EMT-driven cellular behavior.