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Tracking the embryonic stem cell transition from ground state pluripotency

By Tüzer Kalkan, Nelly Olova, Mila Roode, Carla Mulas, Heather J. Lee, Isabelle Nett, Hendrik Marks, Rachael Walker, Hendrik G Stunnenberg, Kathryn S. Lilley, Jennifer Nichols, Wolf Reik, Paul Bertone, Austin Smith

Posted 08 Dec 2016
bioRxiv DOI: 10.1101/092510 (published DOI: 10.1242/dev.142711)

Mouse embryonic stem (ES) cells are locked into self-renewal by shielding from inductive cues. Release from this ground state in minimal conditions offers a system for delineating developmental progression from naive pluripotency. Here we examined the initial transition of ES cells. The population behaves asynchronously. We therefore exploited a short-half-life Rex1::GFP reporter to isolate cells either side of exit from naive status. Extinction of ES cell identity in single cells is acute. It occurs only after near-complete elimination of naive pluripotency factors, but precedes appearance of lineage specification markers. Cells newly departed from the ES cell state exhibit global transcriptome features consistent with features of early post-implantation epiblast and distinct from primed epiblast. They also exhibit a genome-wide increase in DNA methylation, intermediate between early and late epiblast. These findings are consistent with the proposition that naive cells transition to a discrete formative phase of pluripotency preparatory to lineage priming.

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