Program in Genes & Development, UT Graduate School in Biomedical Sciences at Houston, Center for Stem Cell & Development Biology, Department of Biochemistry & Molecular Biology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA, Division of Biomedical Informatics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA and Dan L. Duncan Cancer Center, Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Nucleic Acids Res. 2014 Jan;42(1):205-23. doi: 10.1093/nar/gkt866. Epub 2013 Sep 27.
How tumor suppressor p53 selectively responds to specific signals, especially in normal cells, is poorly understood. We performed genome-wide profiling of p53 chromatin interactions and target gene expression in human embryonic stem cells (hESCs) in response to early differentiation, induced by retinoic acid, versus DNA damage, caused by adriamycin. Most p53-binding sites are unique to each state and define stimulus-specific p53 responses in hESCs. Differentiation-activated p53 targets include many developmental transcription factors and, in pluripotent hESCs, are bound by OCT4 and NANOG at chromatin enriched in both H3K27me3 and H3K4me3. Activation of these genes occurs with recruitment of p53 and H3K27me3-specific demethylases, UTX and JMJD3, to chromatin. In contrast, genes associated with cell migration and motility are bound by p53 specifically after DNA damage. Surveillance functions of p53 in cell death and cell cycle regulation are conserved in both DNA damage and differentiation. Comparative genomic analysis of p53-targets in mouse and human ESCs supports an inter-species divergence in p53 regulatory functions during evolution. Our findings expand the registry of p53-regulated genes to define p53-regulated opposition to pluripotency during early differentiation, a process highly distinct from stress-induced p53 response in hESCs.
肿瘤抑制因子 p53 如何选择性地响应特定信号，尤其是在正常细胞中，目前还了解甚少。我们在人类胚胎干细胞（hESC）中进行了全基因组范围的 p53 染色质相互作用和靶基因表达谱分析，以研究细胞早期分化（由维甲酸诱导）和 DNA 损伤（由阿霉素引起）对 p53 的影响。大多数 p53 结合位点是每种状态所特有的，可定义 hESC 中刺激特异性的 p53 反应。分化激活的 p53 靶标包括许多发育转录因子，在多能性 hESC 中，这些靶标由 OCT4 和 NANOG 与富含 H3K27me3 和 H3K4me3 的染色质结合。这些基因的激活伴随着 p53 和 H3K27me3 特异性去甲基酶 UTX 和 JMJD3 向染色质的募集。相比之下，与细胞迁移和运动相关的基因在 DNA 损伤后才被 p53 特异性地结合。p53 在细胞死亡和细胞周期调控中的监控功能在 DNA 损伤和分化中都得到了保守。对小鼠和人类 ESC 中 p53 靶基因的比较基因组分析支持在进化过程中 p53 调控功能的种间差异。我们的研究结果扩展了 p53 调控基因的登记册，定义了 p53 在早期分化过程中对多能性的调控拮抗作用，这一过程与 hESC 中应激诱导的 p53 反应有很大的不同。
