CRISPR-based editing reveals edge-specific effects in biological networks

Abstract

Unraveling the properties of biological networks is central to understanding normal and disease cellular phenotypes. Networks consist of functional elements (nodes) that form a variety of diverse connections (edges) with each node being a hub for multiple edges. Herein, in contrast to node-centric network perturbation and analysis approaches, we present a high-throughput CRISPR-based methodology for delineating the role of network edges. Ablation of network edges using a library targeting 93 miRNA target sites in 71 genes reveals numerous edges that control, with variable importance, cellular survival under stress. To compare the impact of removing nodes versus edges in a biological network, we dissect a specific p53-microRNA pathway. In summary, we demonstrate that network edges are critical to the function and stability of biological networks. Our results introduce a novel genetic screening opportunity via edge ablation and highlight a new dimension in biological network analysis.