Stochastic transcription in the p53-mediated response to DNA damage is modulated by burst frequency.,Molecular Systems Biology

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Stochastic transcription in the p53-mediated response to DNA damage is modulated by burst frequency.
Molecular Systems Biology ( IF 8.5 ) Pub Date : 2019-12-01 , DOI: 10.15252/msb.20199068
Dhana Friedrich _{1,

2,

3} , Laura Friedel ₁ , Ana Finzel ₂ , Andreas Herrmann ₃ , Stephan Preibisch _{2,

4} , Alexander Loewer _{1,

2}

Affiliation

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.

中文翻译：

p53介导的对DNA损伤的应答中的随机转录受猝发频率的调节。

已经描述了对于不同的哺乳动物细胞系和许多启动子的不连续转录。但是，我们对各个启动子的活性如何通过来自转录因子的动态信号输入进行调节的知识是有限的。为了解决这个问题，我们表征了所选靶基因的活性，该靶基因受电离辐射的抑制作用p53的脉冲积累调节。我们通过smFISH在单细胞水平上进行了时间分辨的基因表达测量，并使用所得数据为启动子活性的数学模型提供了依据。我们发现p53目标启动子受随机突发的频率调制调节，并且可以沿着基因表达的三种原型分组。这些原型的出现不能仅通过核p53丰度或总p53的启动子结合来解释。相反，我们提供了证据表明p53的C端赖氨酸残基的时变乙酰化状态对于随机爆发的基因特异性调节至关重要。

更新日期：2019-12-02

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