Genome Integrity & Structural Biology Laboratory, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA.
Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA.
Nucleic Acids Res. 2018 Sep 19;46(16):8153-8167. doi: 10.1093/nar/gky720.
p53 transcriptional networks are well-characterized in many organisms. However, a global understanding of requirements for in vivo p53 interactions with DNA and relationships with transcription across human biological systems in response to various p53 activating situations remains limited. Using a common analysis pipeline, we analyzed 41 data sets from genome-wide ChIP-seq studies of which 16 have associated gene expression data, including our recent primary data with normal human lymphocytes. The resulting extensive analysis, accessible at p53 BAER hub via the UCSC browser, provides a robust platform to characterize p53 binding throughout the human genome including direct influence on gene expression and underlying mechanisms. We establish the impact of spacers and mismatches from consensus on p53 binding in vivo and propose that once bound, neither significantly influences the likelihood of expression. Our rigorous approach revealed a large p53 genome-wide cistrome composed of >900 genes directly targeted by p53. Importantly, we identify a core cistrome signature composed of genes appearing in over half the data sets, and we identify signatures that are treatment- or cell-specific, demonstrating new functions for p53 in cell biology. Our analysis reveals a broad homeostatic role for human p53 that is relevant to both basic and translational studies.
p53 转录网络在许多生物中都得到了很好的描述。然而，对于在各种 p53 激活情况下，p53 与 DNA 的体内相互作用以及与转录的关系在人类生物系统中的需求，我们仍缺乏全面的理解。我们使用通用的分析流程分析了 41 个来自全基因组 ChIP-seq 研究的数据组，其中 16 个具有相关的基因表达数据，包括我们最近用正常人淋巴细胞进行的原始数据。通过 UCSC 浏览器在 p53 BAER 中心访问这一广泛的分析结果，为我们提供了一个强大的平台，可用于描述整个人类基因组中的 p53 结合情况，包括对基因表达的直接影响和潜在机制。我们确定了间隔区和与共识的错配对 p53 体内结合的影响，并提出一旦结合，两者都不会显著影响表达的可能性。我们严格的方法揭示了一个由 >900 个直接受 p53 靶向的基因组成的大型 p53 全基因组顺式调控元件。重要的是，我们确定了一个由出现在一半以上数据集的基因组成的核心顺式调控元件特征，并确定了与治疗或细胞特异性相关的特征，这证明了 p53 在细胞生物学中的新功能。我们的分析揭示了人类 p53 的广泛的稳态作用，这与基础研究和转化研究都相关。
