P53 drives a transcriptional program that elicits a non-cell-autonomous response and alters cell state in vivo

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Abstract

Cell stress and DNA damage activate the tumor suppressor p53, triggering transcriptional activation of a myriad of target genes. The molecular, morphological, and physiological consequences of this activation remain poorly understood in vivo. We activated a p53 transcriptional program in mice by deletion of Mdm2, a gene that encodes the major p53 inhibitor. By overlaying tissue-specific RNA-sequencing data from pancreas, small intestine, ovary, kidney, and heart with existing p53 chromatin immunoprecipitation (ChIP) sequencing, we identified a large repertoire of tissuespecific p53 genes and a common p53 transcriptional signature of seven genes, which included Mdm2 but not p21. Global p53 activation caused a metaplastic phenotype in the pancreas that was missing in mice with acinar-specific p53 activation, suggesting non-cell-autonomous effects. The p53 cellular response at singlecell resolution in the intestine altered transcriptional cell state, leading to a proximal enterocyte population enriched for genes within oxidative phosphorylation pathways. In addition, a population of active CD8+ T cells was recruited. Combined, this study provides a comprehensive profile of the p53 transcriptional response in vivo, revealing both tissue-specific transcriptomes and a unique signature, which were integrated to induce both cell-autonomous and non-cell-autonomous responses and transcriptional plasticity.

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Moyer, S. M., Wasylishen, A. R., Qi, Y., Fowlkes, N., Su, X., & Lozano, G. (2020). P53 drives a transcriptional program that elicits a non-cell-autonomous response and alters cell state in vivo. Proceedings of the National Academy of Sciences of the United States of America, 117(38), 23663–23673. https://doi.org/10.1073/pnas.2008474117

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