Deciphering global transcriptional dynamics coordinated by gene-gene regulatory interactions using single-cell data

Area of Science:

• Molecular Biology
• Systems Biology
• Genomics

Background:

• Transcription is a dynamic, stochastic process occurring in bursts, influenced by gene regulatory interactions.
• Cell-to-cell heterogeneity arises from these bursting dynamics, but genome-wide understanding is limited.
• Mechanistic insights into how regulatory networks shape transcriptional bursting are lacking.

Purpose of the Study:

• To develop a genome-wide, mechanistic framework for inferring regulatory interactions and transcriptional bursting kinetics.
• To provide a unified model for analyzing transcriptional bursting dynamics from single-cell data.
• To uncover genome-wide regulatory principles governing gene expression bursts.

Main Methods:

• Introduced BurstLink, a statistical-mechanistic framework integrating gene regulatory networks and transcriptional bursting.
• Utilized reweighted mutual information to quantify regulatory strength and infer directionality and interaction types.
• Applied the framework to single-cell data from mouse embryonic fibroblasts.

Main Results:

• Identified genome-wide regulatory mechanisms influencing transcriptional bursting dynamics.
• Found downstream target genes have higher burst frequency and variability than upstream transcription factors.
• Demonstrated that transcription factor binding affinity correlates with target gene burst frequency and size.
• Showed positive regulation increases target gene burst frequency and variability, unlike negative regulation.

Conclusions:

• BurstLink deciphers general principles of global transcriptional dynamics.
• The study provides novel biological insights into cell fate decisions driven by transcriptional bursting.
• Revealed distinct roles of positive and negative regulation in modulating transcriptional bursting.