Global transcription regulation revealed from dynamical correlations in time-resolved single-cell RNA-sequencing

Abstract

AbstractSingle-cell transcriptomics reveals significant variations in the transcriptional activity across cells. Yet, it remains challenging to identify mechanisms of transcription dynamics from static snapshots. It is thus still unknown what drives global transcription dynamics in single cells. We present a stochastic model of gene expression in growing and dividing cells that harnesses temporal dimensions of single-cell RNA-sequencing through metabolic labelling protocols and cell cycle reporters. We develop a parallel and highly scalable Approximate Bayesian Computation method that corrects for technical variation and accurately quantifies absolute burst frequency, burst size and degradation rate at a transcriptome-wide scale. Using Bayesian model selection, we reveal scaling between transcription rates and cell size and unveil waves of gene regulation across the cell cycle-dependent transcriptome. Our study shows that stochastic modelling of dynamical correlations identifies global mechanisms of transcription regulation. We illustrate how mechanistic modelling and amortised inference can efficiently integrate distributions across time, modalities and conditions. Our framework thus provides a versatile tool to uncover how global transcriptional dynamics is orchestrated genome-wide in single cells.