RT Journal Article SR Electronic T1 Tracking the embryonic stem cell transition from ground state pluripotency JF bioRxiv FD Cold Spring Harbor Laboratory SP 092510 DO 10.1101/092510 A1 Tüzer Kalkan A1 Nelly Olova A1 Mila Roode A1 Carla Mulas A1 Heather J. Lee A1 Isabelle Nett A1 Hendrik Marks A1 Rachael Walker A1 Hendrik G. Stunnenberg A1 Kathryn S. Lilley A1 Jennifer Nichols A1 Wolf Reik A1 Paul Bertone A1 Austin Smith YR 2016 UL http://biorxiv.org/content/early/2016/12/08/092510.abstract 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.