Distinct Regulatory Mechanisms and Functions for p53-Activated and p53-Repressed DNA Damage Response Genes in Embryonic Stem Cells
Open accessAbstract
p53 is critical in regulating the differentiation of ES and induced pluripotent stem (iPS) cells. Here, we report a whole-genome study of p53-mediated DNA damage signaling in mouse ES cells. Systems analyses reveal that binding of p53 at the promoter region significantly correlates with gene activation but not with repression. Unexpectedly, we identify a regulatory mode for p53-mediated repression through interfering with distal enhancer activity. Importantly, many ES cell-enriched core transcription factors are p53-repressed genes. Further analyses demonstrate that p53-repressed genes are functionally associated with ES/iPS cell status while p53-activated genes are linked to differentiation. p53-activated genes and -repressed genes also display distinguishable features of expression levels and epigenetic markers. Upon DNA damage, p53 regulates the self-renewal and pluripotency of ES cells. Together, these results support a model where, in response to DNA damage, p53 affects the status of ES cells through activating differentiation-associated genes and repressing ES cell-enriched genes.
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In mouse embryonic stem cells, a p53-induced programme activates differentiation genes and represses pluripotency genes.
“Notably, in mouse embryonic stem cells, a p53-induced programme is associated with transcriptional activation of a differentiation programme and the repression of pluripotent stem cell genes130.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [130]
Gene downregulation through distal enhancer interference by p53 binding has been reported for mouse embryonic stem cells.
“gene downregulation through distal enhancer interference by p53 binding has been reported for mouse embryonic stem cells,17”
From Census and evaluation of p53 target genes (2017) · cites this paper as [17]
Recent genome-wide analyses have identified from one hundred up to thousands of potential p53 target genes.
“Recent genome-wide analyses have identified from one hundred16 up to thousands17 of potential p53 target genes.”
From Census and evaluation of p53 target genes (2017) · cites this paper as [17]
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- Authors
- Li, M., He, Y., Dubois, W., Wu, X., Shi, J., & Huang, J.
- Affiliations
- National Cancer Institute (US)
- Frederick National Laboratory for Cancer Research (US)
- Corresponding author
- Huang, Jing
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 46
- Issue
- 1
- Pages
- 30-42
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3327774
- OpenAlex
- W1966791160
- Cited by
- 264
- References
- 47
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 12 · 2023: 28 · 2022: 9 · 2021: 23 · 2020: 19 · 2019: 21 · 2018: 11 · 2017: 24 · 2016: 23 · 2015: 23 · 2014: 26 · 2013: 24 · 2012: 9
- FWCI
- 10.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99 CA999999)
- National Cancer Institute (ZIABC011158, HHSN261200800001E), ZIABC011260)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- p53, DNA damage response, embryonic stem cells, induced pluripotent stem cells, transcriptional repression, enhancer activity, pluripotency, self-renewal, cell differentiation, epigenetic regulation, whole genome expression profiling
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, DNA Damage, Gene Expression Regulation, Models, Biological, Repressor Proteins, Tumor Suppressor Protein p53, Genome, Response Elements, Pluripotent Stem Cells, Mice, Embryonic Stem Cells
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