ORIGINAL RESEARCH article

Front. Cell Dev. Biol.

Sec. Signaling

Volume 13 - 2025 | doi: 10.3389/fcell.2025.1603603

This article is part of the Research TopicSystems Biology: Encoding Cell Signaling with Quantitative Molecular Tools and ModelsView all 5 articles

Decoding stimulus-specific regulation of promoter activity of p53 target genes

Provisionally accepted
Flavia  VigliottiFlavia Vigliotti1Nicolai  EngelmannNicolai Engelmann2Mark  Sinzger-D´AngeloMark Sinzger-D´Angelo2Heinz  KoepplHeinz Koeppl2*Alexander  LoewerAlexander Loewer1*
  • 1Department of Biology, Darmstadt University of Technology, Darmstadt, Germany
  • 2Department of Electrical Engineering and Information Technology, Darmstadt University of Technology, Darmstadt, Hesse, Germany

The final, formatted version of the article will be published soon.

The tumor suppressor p53 plays a crucial role in maintaining genome integrity in response to exogenous or endogenous stresses. The dynamics of p53 activation are stimulus-and cell typedependent and regulate cell fate. Acting as a transcription factor, p53 induces the expression of target genes involved in apoptosis, cell cycle arrest and DNA repair. However, transcription is not a deterministic process, but rather occurs in bursts of activity and promoters switch stochastically between ON and OFF states, resulting in substantial cell-to-cell variability. Here, we characterized how stimulus-dependent p53 dynamics are converted into specific gene regulation patterns by inducing diverse forms of DNA damage ranging from ionizing and UV radiation to clinically relevant chemotherapeutics. We employed single molecule fluorescence in-situ hybridization (smFISH) to quantify the activity of target gene promoters at the single-cell and single-molecule level. To analyse this comprehensive data set, we developed a new framework for determining parameters of stochastic gene expression by Bayesian inference. Using this combined theoretical and experimental approach, we revealed that features of promoter activity are differentially regulated depending on the target gene and the nature and extent of the DNA damage induced. Indeed, stimulus-specific stochastic gene expression is predominantly regulated by promoter activation and deactivation rates. Interestingly, we found that in many situations, transcriptional activity was uncoupled from the total amount of p53 and the fraction bound to DNA, highlighting that transcriptional regulation by p53 is a multidimensional process. Taken together, our study provides insights into p53-mediated transcriptional regulation as an example of a dynamic transcription factor that shapes the cellular response to DNA damage.

Keywords: stochastic transcription, Bayesian inference, telegraph model, SmFISH, p53 signalling

Received: 31 Mar 2025; Accepted: 30 May 2025.

Copyright: © 2025 Vigliotti, Engelmann, Sinzger-D´Angelo, Koeppl and Loewer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Heinz Koeppl, Department of Electrical Engineering and Information Technology, Darmstadt University of Technology, Darmstadt, 64289, Hesse, Germany
Alexander Loewer, Department of Biology, Darmstadt University of Technology, Darmstadt, Germany

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