Transiently increased intercommunity regulation characterizes concerted cell phenotypic transition

ABSTRACT Phenotype transition takes place in many biological processes such as differentiation and reprogramming. A fundamental question is how cells coordinate switching of expressions of clusters of genes. Through analyzing single cell RNA sequencing data in the framework of transition path theory, we studied how such a genome-wide expression program switching proceeds in five different cell transition processes. For each process we reconstructed a reaction coordinate describing the transition progression, and inferred the gene regulation network (GRN) along the reaction coordinate. In all processes we observed common pattern that the overall effective number and strength of regulation between different communities increase first and then decrease. The change accompanies with similar change of the GRN frustration, defined as overall conflict between the regulation received by genes and their expression states, and GRN heterogeneity. While studies suggest that biological networks are modularized to contain perturbation effects locally, our analyses reveal a general principle that during a cell phenotypic transition, intercommunity interactions increase to concertedly coordinate global gene expression reprogramming, and canalize to specific cell phenotype as Waddington visioned.