TY - JOUR
T1 - P53 drives a transcriptional program that elicits a non-cell-autonomous response and alters cell state in vivo
AU - Moyer, Sydney M.
AU - Wasylishen, Amanda R.
AU - Qi, Yuan
AU - Fowlkes, Natalie
AU - Su, Xiaoping
AU - Lozano, Guillermina
N1 - Funding Information:
We thank Aislyn Schalck and members of the laboratory of G.L. for helpful discussions. This research was supported by NIH Grant CA47296 (to G.L.), Cancer Prevention and Research Institute of Texas Integrated Single Cell Genomics Core Facility Grant RP180684, and Cancer Center Support Grant to MD Anderson Cancer Center CA16672 (it partially supports The MD Anderson Advanced Technology Genomics Core, which conducted all sequencing). S.M.M. was supported in part by the Dr. John J. Kopchick Fellowship and the American Legion Auxiliary Fellowship for Cancer Research.
Funding Information:
ACKNOWLEDGMENTS. We thank Aislyn Schalck and members of the laboratory of G.L. for helpful discussions. This research was supported by NIH Grant CA47296 (to G.L.), Cancer Prevention and Research Institute of Texas Integrated Single Cell Genomics Core Facility Grant RP180684, and Cancer Center Support Grant to MD Anderson Cancer Center CA16672 (it partially supports The MD Anderson Advanced Technology Genomics Core, which conducted all sequencing). S.M.M. was supported in part by the Dr. John J. Kopchick Fellowship and the American Legion Auxiliary Fellowship for Cancer Research.
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/9/22
Y1 - 2020/9/22
N2 - 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.
AB - 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.
KW - Mdm2
KW - Signature
KW - Single-cell sequencing
KW - Transcriptome
KW - p53
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U2 - 10.1073/pnas.2008474117
DO - 10.1073/pnas.2008474117
M3 - Article
C2 - 32900967
AN - SCOPUS:85091596402
SN - 0027-8424
VL - 117
SP - 23663
EP - 23673
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 38
ER -