In Vivo Genome-Wide Analyses of the Drosophila p53 Transcriptional Network

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p53 is the most commonly mutated gene in human cancers. Despite decades of p53 studies we do not fully understand how p53 suppresses tumors. Similar to human p53, the Drosophila counterpart is a transcription factor that can respond to genotoxic stress and promote adaptive responses at the cellular level. Our lab has leveraged the powerful genetics of Drosophila to study p53 functions in vivo. In the context of the developing fly, p53 robustly activates important apoptotic genes in response to DNA damage to promote cell death. In the embryo model, we discovered an important p53 enhancer that forms chromatin contacts through long genomic distances and enables p53 to activate various genes. How p53 programs are adapted in different cellular contexts is poorly understood. In my dissertation work I examined two layers of p53 regulation, long-range enhancer looping and p53 DNA occupancy. To further examine enhancer looping, I exploited the established embryo model and the well characterized p53 reaper enhancer. At the single cell resolution, I demonstrated that the p53 enhancer can contact multiple targets simultaneously; however these multigenic complexes appear in low frequency. I also have preliminary genome-wide data suggesting in embryos this p53 enhancer contacts additional p53 targets. In addition, through genome-scale analyses I dissected novel p53 programs in a postmitotic model (the Drosophila head). Interestingly, postmitotic p53 programs are distinct from networks described in developing cells. I found that the canonical p53 apoptotic program is unresponsive in Drosophila heads, establishing this system as an ideal in vivo model to study alternate functions of p53. To determine how p53 differential programs are specified, I tested two distinct mechanisms for tissue specific target activation, p53 enhancer looping and DNA binding. Interestingly, I observed no change in enhancer looping to cell death targets in heads. However, I did detect loss of p53 enhancer binding. Lastly, I integrated genome-wide analyses of p53 DNA occupancy and transcriptional control in embryos and heads. Interestingly, I found that at the genome-scale p53 binding landscapes poorly correlate with nearby transcriptional effects, indicating that p53 enhancers could be generally acting through long distances.

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