Transiently increased coordination in gene regulation during cell phenotypic transitions

Area of Science:

• Genomics
• Systems Biology
• Developmental Biology

Background:

• Phenotype transitions, such as cell differentiation and reprogramming, are fundamental biological processes.
• Understanding how cells coordinate the switching of gene expression clusters during these transitions is a key challenge.

Purpose of the Study:

• To investigate the genome-wide gene expression program switching during five distinct cell transition processes.
• To identify common principles governing gene regulatory network dynamics during cellular transitions.

Main Methods:

• Analysis of single-cell RNA sequencing data using transition path theory.
• Reconstruction of reaction coordinates to describe transition progression.
• Inference of gene regulatory networks along these reaction coordinates.

Main Results:

• A common pattern was observed across all five processes: the effective number and strength of regulatory interactions between gene communities initially increased and subsequently decreased.
• This dynamic was mirrored by changes in gene regulatory network frustration, indicating shifts in the conflict between gene regulation and expression states.
• Intercommunity interactions intensify during phenotypic transitions to orchestrate global gene expression reprogramming.

Conclusions:

• Cellular phenotypic transitions are characterized by a dynamic regulation of intercommunity interactions within gene regulatory networks.
• Increased intercommunity interactions facilitate concerted global gene expression reprogramming, guiding cells toward a specific phenotype, aligning with Waddington's conceptualization.
• This study reveals a general principle of coordinated gene expression regulation during cell fate determination.