Abstract
Background Cell-to-cell heterogeneity in gene expression even occurs among cells of the same type in a similar environment. Transcriptional bursting is considered a contributing factor to the heterogeneity, but it remains elusive how the kinetic properties of transcriptional bursting (e.g., burst size, burst frequency, and noise induced by transcriptional bursting) are regulated in mammalian cells.
Results In this study, we performed a genome-wide analysis of transcriptional bursting in mouse embryonic stem cells (mESCs) using single-cell RNA-sequencing. We found that the kinetics of transcriptional bursting was determined by a combination of promoter and gene body binding proteins, including polycomb repressive complex 2 and transcription elongation-related factors. Furthermore, large-scale CRISPR-Cas9-based screening and functional analysis revealed that the Akt/MAPK signaling pathway regulated bursting kinetics by modulating transcription elongation efficiency.
Conclusions We found that the kinetics of transcriptional bursting was determined by a combination of promoter and gene body binding proteins, including PRC2 and transcription elongation-related factors. These data uncover key molecular determinants controlling transcriptional bursting and cell-to-cell gene expression noise in mammalian cells.