p53 Pulses Diversify Target Gene Expression Dynamics in an mRNA Half-Life-Dependent Manner and Delineate Co-regulated Target Gene Subnetworks.
p53 Pulses Diversify Target Gene Expression Dynamics in an mRNA Half-Life-Dependent Manner and Delineate Co-regulated Target Gene Subnetworks.
复制标题
p53以mRNA半衰期依赖性方式脉冲靶基因表达动力学多样化，并描绘了共同调节的靶基因子网。
DOI：
10.1016/j.cels.2016.03.006
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发表时间：
2016-04-27
期刊：
影响因子：
9.3
通讯作者：
Batchelor E
中科院分区：
文献类型：
--
作者：
Porter JR;Fisher BE;Batchelor E
转录因子p53通过在一系列固定振幅、持续时间和周期的脉冲中增加浓度来响应DNA双链断裂。p53脉冲如何影响p53靶基因表达的动力学尚不清楚。在这里，我们表明，在散装细胞群体中，p53靶基因表达的模式集群成组与刻板的时间行为，包括脉冲和上升的动态。这些行为在统计学上与靶基因的mRNA衰减率相关：短的mRNA半衰期产生基因表达的脉冲。这种关系可以通过单个细胞和细胞群体中p53依赖性基因表达的数学模型来概括。单细胞转录谱表明，一个子集的p53靶基因的表达是协调跨时间内的单细胞; p53脉冲衰减这种协调。这些结果有助于描述p53如何协调复杂的DNA损伤反应，并深入了解脉动信号通路的功能。
The transcription factor p53 responds to DNA double strand breaks by increasing in concentration in a series of pulses of fixed amplitude, duration, and period. How p53 pulses influence the dynamics of p53 target gene expression is not understood. Here we show that in bulk cell populations, patterns of p53 target gene expression cluster into groups with stereotyped temporal behaviors, including pulsing and rising dynamics. These behaviors correlate statistically with the mRNA decay rates of target genes: short mRNA half-lives produce pulses of gene expression. This relationship can be recapitulated by mathematical models of p53-dependent gene expression in single cells and cell populations. Single-cell transcriptional profiling demonstrates that expression of a subset of p53 target genes is coordinated across time within single cells; p53 pulsing attenuates this coordination. These results help delineate how p53 orchestrates the complex DNA damage response and give insight into the function of pulsatile signaling pathways.