Abstract 4525: Distinctive chromatin organization of p53 binding sites in normal and cancer cells

Abstract

Abstract The tumor suppressor p53 is arguably one of best known proteins in humans, which induces or represses hundreds of genes to prevent tumor development. Now, it becomes clear where p53 binds across the human genome and how it regulates gene expression. Recent studies have established that p53 can access its target sites on the nucleosomal DNA and the rotational positioning of a nucleosome is critical to determine the accessibility of p53 sites. We have found that p53 response elements (REs) associate with cell cycle arrest such as p21 REs are likely to be exposed on the nuclesomal surface. However, it remains unclear if other chromatin elements such as histone modifications and DNA methylation affect p53 in vivo binding and if such chromatin organization differs in normal cells versus cancer cells. We analyzed the pre-existing chromatin landscape of thousands of p53 binding sites identified so far in normal (GM12878) and cancer (K562) cells. The p53 sites derived from the normal cells are often found in the vicinity of the transcription start sites (TSSs) of nearby genes, characterized with relative low nucleosome occupancy, high levels of transcriptionally active histone marks such as H3K4me3 and low levels of DNA methylation. By contrast, the p53 sites found in the cancer cells are located remotely from TSSs, with relatively high nucleosome occupancy, low levels of H3K4me3 and DNA methylation. The shift in p53 genomic binding patterns in the normal and cancer cells reflects the cancer-associated epigenetic dysregulation. Overall, in contrast to most of DNA-binding transcriptional factors, p53 binding sites occur in nucleosome-enriched regions. These findings indicate that p53 belong to a set of transcription factors including the pluripotency factors Oct4, Sox2 and Klf4 that can directly interact with nucleosomes in the context of chromatin. Citation Format: Feng Cui, Peter LoVerso, Feifei Bao. Distinctive chromatin organization of p53 binding sites in normal and cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4525.