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p53, a New Master Regulator of Stem Cell Differentiation

This graphic shows that in response to DNA damage, p53 represses many embryonic-stem-cell (ES)-associated genes, such as Oct4, Sox2, Nanog, Sall4, Esrrb, Sall4, Utf1, Prdm14, n-Myc and c-Myc. This repression involves genome-wide p53 binding at the promoter, gene body and distal regions of thousands of genes.
The graphic above represents how p53 connects its DNA damage signaling with pluripotency in embryonic stem cells (ES). p53 represses many embryonic-stem-cell (ES)-associated genes by binding at the promoter region, gene body and distal regions of thousands of genes.

When the genome is damaged, a key player in stabilizing and maintaining genomic integrity is a protein called p53.  This protein can activate or shut down gene activity in response to DNA damage.  But how exactly does p53 accomplish its task? This question has yet to be answered completely at the molecular level.   

Aware that p53 regulates the differentiation of embryonic stem cells (ES) and induced pluripotent stem (iPS) cells in response to genomic damage, Drs. Mangmang Li, Ph.D., and Jing Huang, Ph.D., working with their colleagues in CCR’s Laboratory of Cancer Biology and Genetics and in the Laboratory of Molecular Technology at Frederick, chose a mouse ES/iPS system to take a molecular look at the effects of p53 in response to DNA damage.  They wanted to know how p53 knows when to activate­­–and when to repress–certain genes. They hoped to discover which genes p53 chooses to regulate in order to restore genomic stability after DNA damage.

Li and Huang used a cutting-edge high-throughput sequencing (ChIP-seq) technology so they could see p53-mediated changes at the genome-wide level following DNA damage.  The research team found that the mechanisms used by p53 to regulate activated genes and repressed genes are drastically different.  They noted that, in response to DNA damage, p53 represses many ES cell- or iPS cell-associated genes, such as Oct4, Sox2, Nanog, Sall4, Esrrb, Sall4, Utf1, Prdm14, n-Myc and c-Myc. In addition, a computational biology approach was used to analyze the genome-wide p53 binding at the promoter, gene body and distal regions of thousands of genes. These analyses revealed a surprising mode of p53-mediated transcription repression in that p53 lands on the distal regions of the repressed genes to shut them down. 

Results of these experiments, published in Molecular Cell, show that p53-activated genes and p53-repressed genes are two functionally separable transcriptional units during ES cell differentiation and somatic cell reprogramming. Li and Huang’s experimental model make it possible to discover the separate molecular activities that underlie p53’s dual roles in response to genomic damage. Once these roles are better understood by studying a genome-wide picture of p53 signaling in ES/iPS cells, the research team will be able to address the link to tumorigenesis.  With the systems biology approaches, they also will be able to decode the complex regulation of p53 through profiling post-translational modifications before and after genomic damage occurs.

Reference
M Li, et al. Distinct regulatory mechanisms and functions of p53-activated and p53-repressed DNA damage response genes in embryonic stem cells. Mol. Cell, March 1, 2012. PubMed Link