Cell phenotypic transition proceeds through concerted reorganization of gene regulatory network

TL;DR

This study investigates how cell phenotype transitions involve coordinated reorganization of gene regulatory networks, revealing a common pattern of frustration dynamics and gene regulation during the process.

Contribution

It introduces a framework combining transition path theory and single-cell RNA sequencing to analyze genome-wide expression changes in cell phenotype transitions.

Findings

Gene regulatory network frustration first increases then decreases during transition

Concerted silencing and activation of gene clusters drive phenotype change

Common patterns observed across different cell transition processes

Abstract

Phenotype transition takes place in many biological processes such as differentiation, and understanding how a cell reprograms its global gene expression profile is a problem of rate theories. A cell phenotype transition accompanies with switching of expression rates of clusters of genes, analogous to domain flipping in an Ising system. Here through analyzing single cell RNA sequencing data in the framework of transition path theory, we set to study how such a genome-wide expression program switching proceeds in three different cell transition processes. For each process after reconstructing a Markov transition model in the cell state space, we formed an ensemble of shortest paths connecting the initial and final cell states, reconstructed a reaction coordinate describing the transition progression, and inferred the gene regulation network (GRN) along the reaction coordinate. In all three processes we observed common pattern that the frustration of gene regulatory network (GRN), defined as overall confliction between the regulation received by genes and their expression states, first increases then decreases when approaching a new phenotype. The results support a mechanism of concerted silencing of genes that are active in the initial phenotype and activation of genes that are active in the final phenotype.