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P53 is essential for DNA methylation homeostasis in naïve embryonic stem cells, and its loss promotes clonal heterogeneity

ABSTRACT: Development of a zygote into a multicellular organism involves many tightly regulated cellular processes, including the epigenetic landscaping of chromatin. When embryonic stem cells (ESCs) are induced to undergo differentiation, the transcriptional network ensuring pluripotency is silenced partly by de novo 5mC DNA methylation. Oxidation of 5mC to hydroxymethylcytosine (5hmC) by the TET enzymes adds another layer of regulation to DNA methylation in ESCs. The increase in 5mC methylation along with a decrease in 5hmC methylation is essential for the cellular commitment towards lineage specification. Recently, crosstalk between the p53 tumor suppressor and DNA methylation was demonstrated, earning p53 the title ‘guardian of the epigenome’. However, the involvement of p53 in regulation of DNA methylation throughout development remained unclear. Here we show that p53 regulates the expression of DNA methyltransferases (DNMTs), which set and maintain 5mC methylation, as well as of TETs, which catalyze 5hmC. In the absence of p53, basal 5mC levels are markedly augmented while hydroxymethylation is compromised. p53 and TETs co-localize on putative enhancers and appear to maintain them unmethylated. Furthermore, p53-/- ESCs acquire an aberrant DNA methylation pattern upon induced differentiation. Importantly, this aberrant pattern is carried over into adult liver. Our results imply that p53 dysfunction may lead to abnormal methylation setting in both ESCs and adult tissue. Thus, loss of p53 function may facilitate cancer development not only by permitting genomic instability but also by enabling epigenetic promiscuity.

ORGANISM(S): Mus musculus

PROVIDER: GSE60209 | GEO | 2017/07/18

SECONDARY ACCESSION(S): PRJNA257753

REPOSITORIES: GEO

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