Identification of universal and cell-type specific p53 DNA binding
Identification of universal and cell-type specific p53 DNA binding
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DOI：
10.1186/s12860-020-00251-8
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发表时间：
2020-02-18
影响因子：
2.8
通讯作者：
Stewart-Ornstein, Jacob
中科院分区：
文献类型：
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作者：
Hafner, Antonina;Kublo, Lyubov;Stewart-Ornstein, Jacob
背景肿瘤抑制基因p53是DNA损伤反应的主要调节因子，并被认为选择性地结合和激活细胞类型特异性的基因表达程序。然而，最近的研究和基因组数据的荟萃分析提出了很大程度上统一的，条件无关的p53结合，从而质疑p53的选择性和细胞类型依赖性功能。结果为了系统地评估p53的细胞类型特异性，我们测量了其与12个p53野生型癌细胞系中DNA的相关性，这些细胞系来自一系列上皮细胞系，对电离辐射有反应。我们发现大多数结合位点在所有细胞系中被占据，然而我们也鉴定了对一个或几个细胞系特异性的结合位点的子集。与共享的p53结合基因组不同，p53与这些非典型结合位点的关联不依赖于染色质可及性，可以通过染色质可及性很好地解释，并可以通过迫使细胞状态变化（如上皮细胞向间充质细胞转化）来调节。结论：我们的研究调和了以前在p53领域相互矛盾的观点，通过证明，虽然大多数p53 DNA结合是保守的跨细胞类型，有一个小的细胞系特异性结合位点，取决于细胞状态。
Background The tumor suppressor p53 is a major regulator of the DNA damage response and has been suggested to selectively bind and activate cell-type specific gene expression programs. However recent studies and meta-analyses of genomic data propose largely uniform, and condition independent p53 binding and thus question the selective and cell-type dependent function of p53. Results To systematically assess the cell-type specificity of p53, we measured its association with DNA in 12 p53 wild-type cancer cell lines, from a range of epithelial linages, in response to ionizing radiation. We found that the majority of bound sites were occupied across all cell lines, however we also identified a subset of binding sites that were specific to one or a few cell lines. Unlike the shared p53-bound genome, which was not dependent on chromatin accessibility, the association of p53 with these atypical binding sites was well explained by chromatin accessibility and could be modulated by forcing cell state changes such as the epithelial-to-mesenchymal transition. Conclusions Our study reconciles previous conflicting views in the p53 field, by demonstrating that although the majority of p53 DNA binding is conserved across cell types, there is a small set of cell line specific binding sites that depend on cell state.