Abstract
Phenotypic switches are associated with alterations in the cell’s gene expression profile and are vital to many aspects of biology. Previous studies have identified local motifs of the genetic regulatory network that could underlie such switches. Recent advancements allowed the study of networks at the global, many-gene, level; however, the relationship between the local and global scales in giving rise to phenotypic switches remains elusive. In this work, we studied the epithelial-mesenchymal transition (EMT) using a gene regulatory network model. This model supports two clusters of stable steady-states identified with the epithelial and mesenchymal phenotypes, and a range of intermediate less stable hybrid states, whose importance in cancer has been recently highlighted. Using an array of network perturbations and quantifying the resulting landscape, we investigated how features of the network at different levels give rise to these landscape properties. We found that local connectivity patterns affect the landscape in a mostly incremental manner; in particular, a specific previously identified double-negative feedback motif is not required when embedded in the full network, because the landscape is maintained at a global level. Nevertheless, despite the distributed nature of the switch, it is possible to find combinations of a few local changes that disrupt it. At the level of network architecture, we identified a crucial role for peripheral genes that act as incoming signals to the network in creating clusters of states. Such incoming signals are a signature of modularity and are expected to appear also in other biological networks. Hybrid states between epithelial and mesenchymal arise in the model due to barriers in the interaction between genes, causing hysteresis at all connections. Our results suggest emergent switches can neither be pinpointed to local motifs, nor do they arise as typical properties of random network ensembles. Rather, they arise through an interplay between the nature of local interactions, and the core-periphery structure induced by the modularity of the cell.
Highlights
Cells undergo transitions between different functional phenotypes in response to environmental cues
To understand how local and global features of genetic networks support a phenotypic switch, we analyzed a model of the epithelial-mesenchymal transition (EMT) network that gives rise to bistable clusters of E/M states intervened by less stable hybrid states
The landscape showed a significant shift towards the E state. This is consistent with the results of Steinway et al [19] who showed that knocking out ZEB1, as well as other E-cadherin suppressors, decreases the probability for EMT transition. These results indicate that while the presence of ZEB1 in the network plays a vital role in the EMT transition, its significance does not stem from the local connectivity in the double negative motif; in particular this motif is not an essential feature in giving rise to the clusters of states in the network model
Summary
Cells undergo transitions between different functional phenotypes in response to environmental cues. Local and global features of genetic networks supporting a phenotypic switch on the role of small, few-component circuits in such transitions. Such network motifs have been identified both in transcriptional and post-transcriptional regulation [1, 2]. When isolated, they have functionalities which may correspond to those of the entire cell state, and provide an intuitive molecular-scale description of cell state transitions. The relationship between local and global properties of the network in giving rise to cell-state transitions remains elusive. How do multiple local motifs upscale their functionality to the entire network? How do multiple local motifs upscale their functionality to the entire network? How sensitive is this upscaling to network global connectivity properties, and to the features of gene-gene interactions?
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