Transiently increased coordination in gene regulation during cell phenotypic transitions.

Phenotype transitions occur in many biological processes such as differentiation and reprogramming. A fundamental question is how cells coordinate switching of gene expression clusters. By analyzing single-cell RNA sequencing data within the framework of transition path theory, we studied the genome-wide expression program switching in five different cell transition processes. For each process we reconstructed a reaction coordinate describing the transition progression, and inferred the gene regulatory network along this reaction coordinate. In all processes we observed a common pattern: the overall effective number and strength of regulation between different communities increase first and then decrease. This change is accompanied by similar changes in gene regulatory network frustration-defined as the overall conflict between the regulation received by genes and their expression states. Complementing previous studies suggesting that biological networks are modularized to contain perturbation effects locally, our analyses on the five cell transition processes likely reveal a general principle: during a cell phenotypic transition, intercommunity interactions increase to concertedly coordinate global gene expression reprogramming and canalize to specific cell phenotype, as Waddington visioned.