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

Transcription is an inherently dynamic and stochastic process that often occurs in bursts, governed by gene-gene regulatory interactions and thereby driving cell-to-cell heterogeneity. However, a genome-wide, mechanistic understanding of how regulatory networks globally shape transcriptional bursting dynamics remains lacking. Here, we present BurstLink, an interpretable and tractable statistical-mechanistic framework that simultaneously infers coupled regulatory interactions and transcriptional bursting kinetics at the genome-wide scale from single-cell data. BurstLink introduces reweighted mutual information to quantify regulatory strength as network edge weights, while jointly inferring regulatory directionality and interaction type for each gene pair within a unified mechanistic model of transcriptional bursting. Applied to mouse embryonic fibroblasts data, BurstLink reveals several genome-wide regulatory mechanisms on transcriptional bursting: downstream target genes exhibit higher burst frequency and gene-expression variability than upstream transcription factor genes; stronger transcription factor binding affinity is associated with lower burst frequency and higher burst size of target genes. Notably, positive regulation primarily enhances the burst frequency and gene-expression variability in target genes, in contrast to negative regulation. In summary, BurstLink deciphers multiple general principles of global transcriptional dynamics, providing novel biological insights into cell fate decisions.