p53 reveals principles of chromatin remodeling and enhancer activation.

Pioneer transcription factors can bind to closed chromatin, initiating its opening and subsequent gene activation. However, the specific features that enable transcription factors to activate particular loci remain largely undefined. Here, we show that the transcription factor p53 unexpectedly initiates epigenetic remodeling at the majority of its binding sites and drives transcription at select loci. Our quantitative epigenetic data reveal that p53 establishes new enhancers, while quantitative transcription initiation analyses indicate that high local p53 abundance and sequence-specific binding are key features of sites where p53 successfully induces transcription. Surprisingly, we observed a spatial overlap between p53 binding sites and transcription initiation sites, suggesting a decoupling of these two events. Our results reveal that p53 activity unfolds across three distinct layers: histone modification, nucleosome eviction, and transcription initiation, with the latter driven by dynamic rather than static p53 DNA binding. These insights expand our understanding of the function of p53 by showing it not only actively initiates transcription but also broadly remodels chromatin. Overall, these findings offer a conceptual framework to explore how transcription factors regulate chromatin states and gene expression.