p53 binding and gene expression profiles in Drosophila postmitotic and embryonic tissue

TP53 is the most frequently mutated gene in human cancers, and despite intensive research efforts, genome-scale studies of p53 function in whole animal models are rare. Yet the need for such in vivo studies is underscored by recent challenges to established models indicating that unappreciated p53 functions contribute to tumor suppression. Here we leveraged the Drosophila system to interrogate p53 function in a postmitotic context. In the developing fly, p53 robustly activates important apoptotic genes in response to radiation-induced DNA damage. We have recently shown that a p53 enhancer near the cell death gene reaper (p53RErpr), forms chromatin contacts and enables p53 target activation through long genomic distances. Interestingly, we found that this canonical p53 apoptotic program fails to activate in response to radiation in postmitotic tissue. Furthermore, the lack of apoptotic responses was not associated with altered chromatin contacts; instead we determined that p53 does not occupy the p53RErpr enhancer in postmitotic tissue. In addition, we conducted RNA-seq and ChIP-seq studies to directly compare the developing and postmitotic tissues, and we determined that p53 regulates distinct transcriptional programs in adult heads, which include DNA repair, metabolism and proteolysis genes. Strikingly, in the postmitotic context p53 binding landscapes were poorly correlated with nearby transcriptional effects, raising the possibility that p53 enhancers could be generally acting through long distances.