Stochastic transcription in the p53-mediated response to DNA damage is modulated by burst frequency.
A549 Cells
Acetylation
Cell Nucleus
/ genetics
DNA Damage
Gene Expression Regulation
Gene Expression Regulation, Neoplastic
/ radiation effects
Gene Regulatory Networks
/ radiation effects
Humans
In Situ Hybridization, Fluorescence
Lysine
/ chemistry
Models, Genetic
Promoter Regions, Genetic
/ radiation effects
Radiation, Ionizing
Single Molecule Imaging
Single-Cell Analysis
Stochastic Processes
Transcription, Genetic
Tumor Suppressor Protein p53
/ chemistry
DNA damage
cellular heterogeneity
p53 signaling
single-cell analysis
stochastic transcription
Journal
Molecular systems biology
ISSN: 1744-4292
Titre abrégé: Mol Syst Biol
Pays: England
ID NLM: 101235389
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
20
06
2019
revised:
04
11
2019
accepted:
07
11
2019
entrez:
31
12
2019
pubmed:
31
12
2019
medline:
25
6
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31885199
doi: 10.15252/msb.20199068
pmc: PMC6886302
doi:
Substances chimiques
TP53 protein, human
0
Tumor Suppressor Protein p53
0
Lysine
K3Z4F929H6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e9068Informations de copyright
© 2019 The Authors. Published under the terms of the CC BY 4.0 license.
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