Cell-cycle dependence of bursty gene expression: insights from fitting mechanistic models to single-cell RNA-seq data

AugustinasSukys

The University of Melbourne

"Cell-cycle dependence of bursty gene expression: insights from fitting mechanistic models to single-cell RNA-seq data"

Many genes are expressed in bursts of transcription, associated with alternating active and inactive promoter states. Such transcriptional bursting is characterised by the burst frequency and burst size, which describe how often a burst occurs and how many transcripts are produced per burst. These two burst parameters offer a simple, intuitive and practical quantitative description of bursty gene expression dynamics. However, a transcriptome-wide picture of how the burst frequency and size are modulated due to gene replication and other cell-cycle dependent factors remains missing. To address this, we fit mechanistic models of gene expression to mRNA count data for thousands of mouse genes, obtained by sequencing of single cells whose cell-cycle position has been inferred previously. Although we observe substantial heterogeneity in transcriptional regulation, we find that upon DNA replication, the genome-wide median burst frequency approximately halves, while the median burst size remains mostly unchanged, thus shedding light on the effect of gene dosage compensation. We show that to accurately estimate the bursting kinetics from sequencing data, mechanistic models must explicitly account for gene copy number variation and extrinsic noise due to factors varying across the cell cycle, whereas correcting for technical noise due to imperfect mRNA capture is less critical.
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