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Nat Struct Mol Biol. 2017 Oct;24(10):840-847. doi: 10.1038/nsmb.3452. Epub 2017 Aug 21.

p53 pulses lead to distinct patterns of gene expression albeit similar DNA-binding dynamics.

Author information

1
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
3
Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
4
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
5
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Abstract

The dynamics of transcription factors play important roles in a variety of biological systems. However, the mechanisms by which these dynamics are decoded into different transcriptional responses are not well understood. Here we focus on the dynamics of the tumor-suppressor protein p53, which exhibits a series of pulses in response to DNA damage. We performed time course RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) measurements to determine how p53 oscillations are linked with gene expression genome wide. We discovered multiple distinct patterns of gene expression in response to p53 pulses. Surprisingly, p53-binding dynamics were uniform across all genomic loci, even for genes that exhibited distinct mRNA dynamics. Using a mathematical model, supported by additional experimental measurements in response to sustained p53 input, we determined that p53 binds to and activates transcription of its target genes uniformly, whereas post-transcriptional mechanisms are responsible for the differences in gene expression dynamics.

PMID:
28825732
PMCID:
PMC5629117
DOI:
10.1038/nsmb.3452
[Indexed for MEDLINE]
Free PMC Article

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