Abstract 4780: Nucleosome organization and accessibility of p53 response elements in the chromatin context

Abstract

Abstract p53 is one of best known human proteins that induces or represses hundreds of genes and plays a pivotal role in preventing tumor development. Recent studies established unambiguously that p53 is a nucleosome-binding protein. The rotational positioning of a nucleosome is critical to determine the accessibility of a p53 site. In particular, the p53 site in a nucleosome is accessible if it is bent in the direction similar to that found in the p53-DNA co-crystals; the site becomes inaccessible if the orientation is changed by ∼180°. Importantly, we have shown that p53 response elements (REs) associated with cell cycle arrest are often exposed on the nucleosomal surface, suggesting a new role of nucleosomes in mediating the p53 binding and subsequent gene induction. The present study aims to make a detailed analysis of nucleosome organization of all p53 functional REs in normal and cancer cells. Published genome-wide nucleosome maps from lymphoblastoid (normal) and K562 (cancer) cell lines are used. In general, the p53 REs are located in nucleosome-enriched regions, in accordance with previous findings that p53 can interact with nucleosomal DNA. At the level of individual sites, the p21 5′ RE resides in a genomic region with high nucleosome occupancy, consistent with earlier studies. The GADD45 RE that was believed to be in nucleosome-free region, is, however, characterized with medium-to-high nucleosome occupancy. To evaluate the accessibility of p53 REs in different functional groups such as cell cycle arrest, apoptosis and DNA repair, we used a more rigorous set of nucleosomes, containing 134 million 147-bp fragments (about 7x genome coverage). The REs in the cell cycle arrest group (such as p21) and the DNA repair group (such as GADD45) are often accessible in the chromatin context, consistent with fast induction of these genes after p53 activation. Interestingly, apoptotic REs are divided - the REs associated with the mitochondrial pathway (BAX and p53AIP1) are accessible, while the REs associated with the death receptor pathway (FAS and KILLER) are inaccessible, suggesting different mechanisms for induction of apoptotic genes in vivo. Finally, we observe a clear correlation between the nucleosome occupancy and accessibility of p53 REs. That is, the REs with the higher nucleosome occupancy tend to be accessible, while the REs with lower nucleosome occupancy are likely to be inaccessible to p53. Citation Format: Peter R. LoVerso, Victor B. Zhurkin, Feng Cui. Nucleosome organization and accessibility of p53 response elements in the chromatin context. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4780. doi:10.1158/1538-7445.AM2015-4780