p53 regulates enhancer accessibility and activity in response to DNA damage.
p53 regulates enhancer accessibility and activity in response to DNA damage.
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DOI：
10.1093/nar/gkx577
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发表时间：
2017-09-29
影响因子：
14.9
通讯作者：
Rinn JL
中科院分区：
文献类型：
--
作者：
Younger ST;Rinn JL
肿瘤抑制因子p53是一种具有良好特性的转录因子，它可以结合基因启动子并调节靶基因的转录以响应DNA损伤。然而，最近的研究表明，p53结合事件主要发生在调节增强子元件内。p53结合对增强子功能的影响尚未得到系统评价。在这里，我们使用一系列大规模平行报告基因检测（MPRAs）与转座酶可接近染色质检测（ATAC-Seq）结合的p53结合序列的增强子活性进行基因组规模的分析。我们发现，大多数序列检查显示p53依赖性增强子活性在DNA损伤反应。此外，我们观察到p53与健康成纤维细胞中的增强子元件结合，并准备响应DNA损伤而快速激活。令人惊讶的是，我们的分析显示，大多数p53结合增强子位于不可接近的染色质区域内。这些增强子的一个大的子集成为访问DNA损伤后，表明p53调节其活性，部分，通过调节染色质的可及性。位于不可接近的染色质内的增强子元件的识别和激活可能有助于p53网络在不同组织和细胞类型的不同染色质景观中发挥作用的能力。
The tumor suppressor p53 is a well-characterized transcription factor that can bind gene promoters and regulate target gene transcription in response to DNA damage. Recent studies, however, have revealed that p53 binding events occur predominantly within regulatory enhancer elements. The effect of p53 binding on enhancer function has not been systematically evaluated. Here, we perform a genome-scale analysis of enhancer activity from p53-bound sequences using a series of massively parallel reporter assays (MPRAs) coupled with the assay for transposase-accessible chromatin (ATAC-Seq). We find that the majority of sequences examined display p53-dependent enhancer activity during the DNA damage response. Furthermore, we observe that p53 is bound to enhancer elements in healthy fibroblasts and poised for rapid activation in response to DNA damage. Surprisingly, our analyses revealed that most p53-bound enhancers are located within regions of inaccessible chromatin. A large subset of these enhancers become accessible following DNA damage indicating that p53 regulates their activity, in part, by modulating chromatin accessibility. The recognition and activation of enhancer elements located within inaccessible chromatin may contribute to the ability of the p53 network to function across the diverse chromatin landscapes of different tissues and cell types.
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