Author ORCID Identifier

0000-0002-2911-4058

Date of Graduation

12-2020

Document Type

Dissertation (PhD)

Program Affiliation

Genes and Development

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Guillermina Lozano, Ph.D.

Committee Member

Michelle C. Barton, Ph.D.

Committee Member

Vicki Huff, Ph.D.

Committee Member

Nancy A. Jenkins, Ph.D.

Committee Member

Marina Y. Konopleva, M.D., Ph.D.

Committee Member

Nicholas E. Navin, Ph.D.

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 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 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 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 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.

Keywords

p53, transcription, Mdm2, single cell RNA-sequencing, transcription factor, tissue-specific, non-cell-autonomous, genetics

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