Interactions of Chromatin Context, Binding Site Sequence Content, and Sequence Evolution in Stress-Induced p53 Occupancy and Transactivation

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It is well established that p53 binds DNA elements near p53 target genes to regulate the response to cellular stress. To assess factors influencing binding to response elements and subsequent gene expression, we have analyzed 2932 p53-occupied response elements (p53REs) in the context of genome-wide chromatin state, DNA accessibility and dynamics, and considered roles for binding-sequence specificity and evolutionary conservation. While p53 occupancy level shows little apparent direct relationship to gene expression change, after grouping expressed genes by their chromatin status at baseline, a relationship between occupancy of p53REs and gene expression change emerged. Analysis of p53RE sequences demonstrated that p53 occupancy was strongly correlated with sequence similarity to p53RE consensus, but surprisingly, was inversely correlated with nucleosome accessibility (DHS) and evolutionary conservation. These data revealed a systematic interaction between p53RE content and chromatin context that affects both quantitative p53 occupancy and the induced transactivation response to exposure. Moreover, this interaction appears to have been tuned via evolutionary events involving transposable elements, which strongly bind p53, but in only a few instances affect gene expression levels. Models of p53-regulated gene expression response that consider both chromatin state and sequence context may prove useful in guiding strategies for cancer prevention or therapy.

Vyšlo v časopise: Interactions of Chromatin Context, Binding Site Sequence Content, and Sequence Evolution in Stress-Induced p53 Occupancy and Transactivation. PLoS Genet 11(1): e32767. doi:10.1371/journal.pgen.1004885
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004885

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