J Mol Biol. 2017 Jul 3. pii: S0022-2836(17)30321-2. doi: 10.1016/j.jmb.2017.06.020. [Epub ahead of print]

Inhibition of cell division and DNA replication impair mouse naïve pluripotency exit.

Waisman A¹, Echegaray CV¹, Solari C¹, Cosentino MS¹, Martyn I², Deglincerti A², Ozair MZ², Matias AR², Barañao L³, Miriuka S⁴, Brivanlou A², Guberman A⁵.

Abstract

The cell cycle has gained attention as a key determinant for cell fate decisions, but the contribution of DNA replication and mitosis in stem cell differentiation has not been extensively studied. To understand if these processes act as 'windows of opportunity' for changes in cell identity, we established synchronized cultures of mouse embryonic stem cells (mESC) as they exit the ground state of pluripotency. We show that initial transcriptional changes in this transition do not require passage through mitosis, and that conversion to primed pluripotency is linked to lineage priming in the G1 phase. Importantly, we demonstrate that impairment of DNA replication severely blocks transcriptional switch to primed pluripotency, even in the absence of p53 activity induced by the DNA damage response. Our data suggest an important role for DNA replication during mESC differentiation, which could shed light on why pluripotent cells are only receptive to differentiation signals during G1, that is, before the S-phase.