TY - JOUR
T1 - p53 is essential for DNA methylation homeostasis in naive embryonic stem cells, and its loss promotes clonal heterogeneity
AU - Tovy, Ayala
AU - Spiro, Adam
AU - McCarthy, Ryan
AU - Shipony, Zohar
AU - Aylon, Yael
AU - Allton, Kendra
AU - Ainbinder, Elena
AU - Furth, Noa
AU - Tanay, Amos
AU - Barton, Michelle
AU - Oren, Moshe
N1 - Publisher Copyright: © 2017 Tovy et al.
PY - 2017/5/15
Y1 - 2017/5/15
N2 - DNA methylation is a key regulator of embryonic stem cell (ESC) biology, dynamically changing between naive, 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 naive 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 "naive" 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.
AB - DNA methylation is a key regulator of embryonic stem cell (ESC) biology, dynamically changing between naive, 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 naive 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 "naive" 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.
UR - http://www.scopus.com/inward/record.url?scp=85021223361&partnerID=8YFLogxK
U2 - https://doi.org/10.1101/gad.299198.117
DO - https://doi.org/10.1101/gad.299198.117
M3 - مقالة
SN - 0890-9369
VL - 31
SP - 959
EP - 972
JO - Genes & development
JF - Genes & development
IS - 10
ER -