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bioRxiv · 10.1101/2020.11.16.384297

TNF stimulation primarily modulates transcriptional burst size of NF-κB-regulated genes

Bass, V. L.·Wong, V. C.·Bullock, M. E.·Gaudet, S.·Miller-Jensen, K.
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Abstract

Cell-to-cell heterogeneity is a characteristic feature of the tumor necrosis factor (TNF)-stimulated inflammatory response mediated by the transcription factor NF-{kappa}B, motivating an exploration of the underlying sources of this noise. Here we combined single-transcript measurements with computational models to study transcriptional noise at six NF-{kappa}B-regulated inflammatory genes. In the basal state, NF-{kappa}B-target genes displayed an inverse correlation between mean and noise. TNF stimulation increased transcription while maintaining noise, except for the most repressed genes. By fitting transcript distributions to a two-state model of promoter activity, we found that TNF primarily stimulated transcription by increasing burst size while maintaining burst frequency. Burst size increases were associated with enrichment of initiated-but-paused RNA polymerase II at the promoter, and blocking the release of paused RNAPII with a small molecule inhibitor decreased TNF-stimulated burst size. Finally, we used a mathematical model to show that TNF positive feedback further amplified gene expression noise resulting from burst-size mediated transcription, leading to diverse TNF functional outputs. Our results reveal potential sources of noise underlying intercellular heterogeneity in the TNF-mediated inflammatory response.

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Bass, V. L., Wong, V. C., Bullock, M. E., Gaudet, S., Miller-Jensen, K.. 2020-11-17. TNF stimulation primarily modulates transcriptional burst size of NF-κB-regulated genes. https://doi.org/10.1101/2020.11.16.384297

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