Local and global features of genetic networks supporting a phenotypic switch

Cells switch between different phenotypes in response to environmental cues. These switches were traditionally attributed to the dynamics of a small set of interacting genes called motifs. Recent advancements in genome and transcriptome measurements allowed the study of such switches on a network-wide scale. However, the relationship between local and global properties of genetic networks in giving rise to phenotypic switches remains elusive.

A prominent switch in development and tumorigenesis that was studied on both levels is the epithelial-mesenchymal transition (EMT). EMT is a reversible process by which epithelial cells, which normally adhere to each other, acquire mesenchymal properties, such as enhanced migratory capacity and invasiveness. At the local level, previous studies showed how such bistability could arise from a double negative motif of essential molecular components. At the global level, bistable clusters of phenotypes with intermediate less stable hybrid states were captured by a Boolean model of the EMT network.

In this work, we utilize the Boolean model to study the relationship between the local and emergent properties of the network. We examine network properties on three levels: the single gene response function, the contribution of a local motif - the double negative feedback loop, and the global network structure. We find that hysteresis at the single gene level and the decomposition of the network into a core and periphery are the main factors contributing to the existence of two clusters of states, while details of connectivity, such as the double negative motif, are not essential.