Kirschner Kristina, Samarajiwa Shamith A, Cairns Jonathan M, Menon Suraj, Pérez-Mancera Pedro A, Tomimatsu Kosuke, Bermejo-Rodriguez Camino, Ito Yoko, Chandra Tamir, Narita Masako, Lyons Scott K, Lynch Andy G, Kimura Hiroshi, Ohbayashi Tetsuya, Tavaré Simon, Narita Masashi
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.
PLoS Genet. 2015 Mar 19;11(3):e1005053. doi: 10.1371/journal.pgen.1005053. eCollection 2015 Mar.
The downstream functions of the DNA binding tumor suppressor p53 vary depending on the cellular context, and persistent p53 activation has recently been implicated in tumor suppression and senescence. However, genome-wide information about p53-target gene regulation has been derived mostly from acute genotoxic conditions. Using ChIP-seq and expression data, we have found distinct p53 binding profiles between acutely activated (through DNA damage) and chronically activated (in senescent or pro-apoptotic conditions) p53. Compared to the classical 'acute' p53 binding profile, 'chronic' p53 peaks were closely associated with CpG-islands. Furthermore, the chronic CpG-island binding of p53 conferred distinct expression patterns between senescent and pro-apoptotic conditions. Using the p53 targets seen in the chronic conditions together with external high-throughput datasets, we have built p53 networks that revealed extensive self-regulatory 'p53 hubs' where p53 and many p53 targets can physically interact with each other. Integrating these results with public clinical datasets identified the cancer-associated lipogenic enzyme, SCD, which we found to be directly repressed by p53 through the CpG-island promoter, providing a mechanistic link between p53 and the 'lipogenic phenotype', a hallmark of cancer. Our data reveal distinct phenotype associations of chronic p53 targets that underlie specific gene regulatory mechanisms.
DNA结合肿瘤抑制因子p53的下游功能因细胞环境而异，最近持续的p53激活与肿瘤抑制和衰老有关。然而，关于p53靶基因调控的全基因组信息大多来自急性基因毒性条件。利用染色质免疫沉淀测序（ChIP-seq）和表达数据，我们发现急性激活（通过DNA损伤）和慢性激活（在衰老或促凋亡条件下）的p53之间存在不同的结合模式。与经典的“急性”p53结合模式相比，“慢性”p53峰与CpG岛密切相关。此外，p53的慢性CpG岛结合在衰老和促凋亡条件之间赋予了不同的表达模式。利用在慢性条件下观察到的p53靶标以及外部高通量数据集，我们构建了p53网络，该网络揭示了广泛的自我调节“p53中心”，其中p53和许多p53靶标可以相互物理作用。将这些结果与公共临床数据集整合，确定了与癌症相关的生脂酶SCD，我们发现它被p53通过CpG岛启动子直接抑制，这为p53与“生脂表型”（癌症的一个标志）之间提供了一种机制联系。我们的数据揭示了慢性p53靶标的不同表型关联，这些关联是特定基因调控机制的基础。
