p53 is essential for DNA methylation homeostasis in naïve embryonic stem cells, and its loss promotes clonal heterogeneity
- Ayala Tovy1,5,
- Adam Spiro2,5,
- Ryan McCarthy3,
- Zohar Shipony2,
- Yael Aylon1,
- Kendra Allton3,
- Elena Ainbinder4,
- Noa Furth1,
- Amos Tanay2,
- Michelle Barton3 and
- Moshe Oren1
- 1Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel;
- 2Department of Computer Science and Applied Mathematics, The Weizmann Institute of Science, Rehovot 76100, Israel;
- 3MD Anderson Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
- 4Department of Life Sciences Core Facilities, The Weizmann Institute of Science, Rehovot 76100, Israel
- Corresponding author: moshe.oren{at}weizmann.ac.il
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↵5 These authors contributed equally to this work.
Abstract
DNA methylation is a key regulator of embryonic stem cell (ESC) biology, dynamically changing between naïve, primed, and differentiated states. The p53 tumor suppressor is a pivotal guardian of genomic stability, but its contributions to epigenetic regulation and stem cell biology are less explored. We report that, in naïve mouse ESCs (mESCs), p53 restricts the expression of the de novo DNA methyltransferases Dnmt3a and Dnmt3b while up-regulating Tet1 and Tet2, which promote DNA demethylation. The DNA methylation imbalance in p53-deficient (p53−/−) mESCs is the result of augmented overall DNA methylation as well as increased methylation landscape heterogeneity. In differentiating p53−/− mESCs, elevated methylation persists, albeit more mildly. Importantly, concomitant with DNA methylation heterogeneity, p53−/− mESCs display increased cellular heterogeneity both in the “naïve” state and upon induced differentiation. This impact of p53 loss on 5-methylcytosine (5mC) heterogeneity was also evident in human ESCs and mouse embryos in vivo. Hence, p53 helps maintain DNA methylation homeostasis and clonal homogeneity, a function that may contribute to its tumor suppressor activity.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.299198.117.
- Received March 22, 2017.
- Accepted May 22, 2017.
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