PT - JOURNAL ARTICLE AU - Tüzer Kalkan AU - Nelly Olova AU - Mila Roode AU - Carla Mulas AU - Heather J. Lee AU - Isabelle Nett AU - Hendrik Marks AU - Rachael Walker AU - Hendrik G. Stunnenberg AU - Kathryn S. Lilley AU - Jennifer Nichols AU - Wolf Reik AU - Paul Bertone AU - Austin Smith TI - Tracking the embryonic stem cell transition from ground state pluripotency AID - 10.1101/092510 DP - 2016 Jan 01 TA - bioRxiv PG - 092510 4099 - http://biorxiv.org/content/early/2016/12/08/092510.short 4100 - http://biorxiv.org/content/early/2016/12/08/092510.full AB - 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 naïve 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 naïve cells transition to a discrete formative phase of pluripotency preparatory to lineage priming.HighlightsThe Rex1 destabilized GFP reporter demarcates naive pluripotency.Exit from the naive state is asynchronous in the population.Transition is relatively acute in individual cells and precedes lineage priming.Transcriptome and DNA methylome reflect events in the pre-gastrulation embryo.