p53 regulates enhancer accessibility and activity in response to DNA damage

Area of Science:

• Molecular Biology
• Genomics
• Cellular Biology

Background:

• The tumor suppressor p53 is a key transcription factor regulating gene expression in response to DNA damage.
• While p53 traditionally binds gene promoters, recent evidence suggests predominant binding at regulatory enhancer elements.
• The functional impact of p53 binding on enhancer activity remains largely uncharacterized.

Purpose of the Study:

• To systematically evaluate the effect of p53 binding on enhancer function genome-wide.
• To investigate how p53 influences enhancer activity and chromatin accessibility during the DNA damage response.

Main Methods:

• Genome-scale analysis of enhancer activity using massively parallel reporter assays (MPRAs).
• Chromatin accessibility profiling via assay for transposase-accessible chromatin (ATAC-Seq).
• Integration of MPRA and ATAC-Seq data to assess p53-dependent enhancer function and chromatin state.

Main Results:

• The majority of p53-bound sequences exhibit p53-dependent enhancer activity following DNA damage.
• p53 binds to enhancer elements in healthy cells, poised for activation upon DNA damage.
• Most p53-bound enhancers reside in inaccessible chromatin regions, with a significant subset becoming accessible post-DNA damage.
• p53 modulates enhancer activity, partly through regulating chromatin accessibility.

Conclusions:

• p53 plays a significant role in regulating enhancer activity, particularly during the DNA damage response.
• p53's ability to activate enhancers within inaccessible chromatin by modulating accessibility is a key finding.
• This mechanism likely contributes to the robustness and adaptability of the p53 network across diverse cellular contexts.