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Published on: May 30, 2012
Sall4 Guides p53-Mediated Enhancer Interference upon DNA Damage in Mouse Embryonic Stem Cells
Lei Wang1, Xiaojun Tan1, Lu Chen1
1Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People's Republic of China.
Abstract:
p53 plays a pivotal role in maintaining the genomic stability of mouse embryonic stem cells (mESCs) through transcriptionally activating and repressing target genes. However, how p53 recognizes its repressed targets remains largely unknown. Herein, we demonstrate that Sall4 negatively regulates DNA damage induced apoptosis (DIA) of mESCs through mediating p53 recruitment to enhancers of ESC-associated genes repressed by p53 from promoters of p53-activated genes. Upon DNA damage, Sall4 is transcriptionally repressed by p53 and plays an anti-apoptotic role without altering p53 activation. Moreover, Sall4 is identified as a novel p53-interacting partner. Consistently, Sall4 exerts its anti-apoptotic function in a p53-dependent manner. Intriguingly, Sall4 depletion not only promotes the transcriptional activation of several p53-regulated pro-apoptotic genes but also compromises p53-mediated repression of ESC master transcription factors in response to DNA damage. Mechanistically, Sall4 balances p53-binding affinity between p53-activated and -repressed genes through tethering p53 to ESC enhancers. In light of our study, Sall4 may contribute to tumorigenesis by antagonizing p53-mediated apoptosis.
Insights
Sall4 antagonizes p53-mediated apoptosis in mouse embryonic stem cells (mESCs) by recruiting p53 to specific gene enhancers. This interaction is crucial for maintaining genomic stability and preventing uncontrolled cell death.
Area of Science:
- Stem cell biology
- Molecular oncology
- Genomics
Background:
- p53 is essential for genomic stability in mouse embryonic stem cells (mESCs).
- p53 regulates gene expression through both activation and repression.
- The mechanism by which p53 recognizes its repressed targets is not fully understood.
Purpose of the Study:
- To investigate the role of Sall4 in regulating p53-mediated apoptosis in mESCs.
- To elucidate how p53 recognizes its repressed targets.
- To understand the mechanism Sall4 uses to modulate p53 activity.
Main Methods:
- Chromatin immunoprecipitation (ChIP) assays to assess p53 recruitment.
- Western blotting to analyze protein interactions and expression levels.
- Quantitative real-time PCR (qRT-PCR) to measure gene expression changes.
Main Results:
- Sall4 negatively regulates DNA damage-induced apoptosis (DIA) in mESCs.
- Sall4 mediates p53 recruitment to enhancers of repressed ESC-associated genes.
- Sall4 interacts with p53 and exerts its anti-apoptotic function in a p53-dependent manner.
- Sall4 depletion enhances p53-activated pro-apoptotic genes and impairs p53-mediated repression of ESC factors.
Conclusions:
- Sall4 acts as a novel p53-interacting partner that balances p53 binding affinity.
- Sall4 tethers p53 to ESC enhancers, influencing p53's regulatory role in response to DNA damage.
- Sall4 may contribute to tumorigenesis by counteracting p53-mediated apoptosis in mESCs.
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