P53 Drives A Transcriptional Program That Elicits A Non-Cell-Autonomous Response and Alters Cell State In Vivo

<p>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 <em>in vivo</em>. We activated a p53 transcriptional program in mice by deletion of <em>Mdm2</em>, a gene which encodes the major p53 inhibitor. By overlaying tissue-specific RNA-sequencing data from pancreas, small intestine, ovary, kidney, and heart with existing p53 ChIP-sequencing, we identified a large repertoire of tissue-specific p53 genes and a common p53 transcriptional signature of seven genes which included <em>Mdm2</em> but not <em>p21</em>. 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 new 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 <em>in vivo</em>, 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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2020

Authors dc:creator

• Moyer, Sydney
• <p>0000-0002-2911-4058</p>

Contributors dc:contributor

• Guillermina Lozano, Ph.D.
• Michelle C. Barton, Ph.D.
• Vicki Huff, Ph.D.

• p53
• transcription
• Mdm2
• single cell RNA-sequencing
• transcription factor
• tissue-specific
• non-cell-autonomous
• genetics
• Cancer Biology
• Cell Biology
• Genomics
• Medicine and Health Sciences
• Molecular Biology
• Molecular Genetics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1048

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2102