| First Author | Moyer SM | Year | 2020 |
| Journal | Proc Natl Acad Sci U S A | Volume | 117 |
| Issue | 38 | Pages | 23663-23673 |
| PubMed ID | 32900967 | Mgi Jnum | J:296363 |
| Mgi Id | MGI:6459217 | Doi | 10.1073/pnas.2008474117 |
| Citation | Moyer SM, et al. (2020) p53 drives a transcriptional program that elicits a non-cell-autonomous response and alters cell state in vivo. Proc Natl Acad Sci U S A 117(38):23663-23673 |
| abstractText | 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 tissue-specific 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 single-cell 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. |
