Abstract
The high proliferation rate of embryonic stem cells (ESCs) is thought to arise partly from very low expression of p21. However, how p21 is suppressed in ESCs has been unclear. We found that p53 binds to the p21 promoter in human ESCs (hESCs) as efficiently as in differentiated human mesenchymal stem cells, however it does not promote p21 transcription in hESCs. We observed an enrichment for both the repressive histone H3K27me3 and activating histone H3K4me3 chromatin marks at the p21 locus in hESCs, suggesting it is a suppressed, bivalent domain which overrides activation by p53. Reducing H3K27me3 methylation in hESCs rescued p21 expression, and ectopic expression of p21 in hESCs triggered their differentiation. Further, we uncovered a subset of bivalent promoters bound by p53 in hESCs that are similarly induced upon differentiation in a p53-dependent manner, whereas p53 promotes the transcription of other target genes which do not show an enrichment of H3K27me3 in ESCs. Our studies reveal a unique epigenetic strategy used by ESCs to poise undesired p53 target genes, thus balancing the maintenance of pluripotency in the undifferentiated state with a robust response to differentiation signals, while utilizing p53 activity to maintain genomic stability and homeostasis in ESCs.
Highlights
The high proliferation rate of embryonic stem cells (ESCs) is thought to arise partly from very low expression of p21
The repression of p21 is thought to be beneficial for Embryonic stem cells (ESCs) to maintain rapid proliferation and genomic integrity by activating CDKs and increasing apoptosis sensitivity, respectively
We found that p21 is epigenetically silenced through H3K27me[3] in human ESCs (hESCs)
Summary
The repression of p21 is thought to be beneficial for ESCs to maintain rapid proliferation and genomic integrity by activating CDKs and increasing apoptosis sensitivity, respectively. At least our data indicated that the upregulation of p21 by p53 is undesired for ESCs to maintain undifferentiated state, suggesting the existence of another layer of mechanisms to suppress the unwanted p21 expression in ESCs. Based on our data, we propose a model in which, while p53 actively induces genes involved in the maintenance of genomic stability and homeostasis of ESCs, a subset of p53 target genes, like p21, are bound by p53 but regulated by epigenetic marks that prevent p53-mediated activation in ESCs (Fig. 5E). We propose a model in which, while p53 actively induces genes involved in the maintenance of genomic stability and homeostasis of ESCs, a subset of p53 target genes, like p21, are bound by p53 but regulated by epigenetic marks that prevent p53-mediated activation in ESCs (Fig. 5E) These genes may otherwise induce undesired changes in ESCs, such as differentiation, preventing apoptosis downstream of DNA damage, decreasing proliferation rate and changing cell cycle profiles. Elucidating how these genes are targeted for specific histone modifications and the consequences of removing their epigenetic marks will further our understanding of pluripotency, metabolism and genomic integrity in ESCs
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