Abstract
Discontinuous transcription has been described for different mammalian cell lines and numerous promoters. However, our knowledge of how the activity of individual promoters is adjusted by dynamic signaling inputs from transcription factors is limited. To address this question, we characterized the activity of selected target genes that are regulated by pulsatile accumulation of the tumor suppressor p53 in response to ionizing radiation. We performed time‐resolved measurements of gene expression at the single‐cell level by smFISH and used the resulting data to inform a mathematical model of promoter activity. We found that p53 target promoters are regulated by frequency modulation of stochastic bursting and can be grouped along three archetypes of gene expression. The occurrence of these archetypes cannot solely be explained by nuclear p53 abundance or promoter binding of total p53. Instead, we provide evidence that the time‐varying acetylation state of p53's C‐terminal lysine residues is critical for gene‐specific regulation of stochastic bursting.
Highlights
Cells constantly respond and adapt to extrinsic and intrinsic stimuli to mediate appropriate cell fate decisions
We provide a quantitative analysis of stochastic p53-dependent gene expression at defined time points during the DNA damage response to ionizing radiation (IR) induced double-strand breaks (DSBs) and reveal archetypes of p53mediated expression dynamics
To characterize how p53 pulses in response to DNA damage affect transcriptional activity at individual promoters in single cells over time, we selected a set of well-characterized p53 targets involved in different cell fate programs (Fig 1B)
Summary
Cells constantly respond and adapt to extrinsic and intrinsic stimuli to mediate appropriate cell fate decisions. Associated transcription factors (TF) often show pulsatile dynamics with time scales ranging from seconds (NFAT4) and minutes (NF-jB, Msn, Erk) to hours (p53) (Lahav et al, 2004; Shankaran et al, 2009; Tay et al, 2010; Hao & O’Shea, 2011; Yissachar et al, 2013) It still remains unclear how molecular circuits convert information from pulsatile TF dynamics to distinguishable expression profiles and how pulses of TFs quantitatively control transcription rates of target genes at individual promoters. P53 dynamics contribute to determining cellular outcomes, as pulsatile p53 accumulation is correlated with transient cell fate programs (cell cycle arrest) in a dose-dependent manner, while sustained p53 levels induce terminal responses (apoptosis, senescence) (Purvis et al, 2012). P53 has been detected at target sites in absence of DNA damage despite low nuclear abundance (Nikulenkov et al, 2012; Younger & Rinn, 2017)
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