Tracking the embryonic stem cell transition from ground state pluripotency.
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 naïve pluripotency. Here, we examine the initial transition process. The ES cell population behaves asynchronously. We therefore exploited a short-half-lifeRex1::GFPreporter to isolate cells either side of exit from naïve 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 display features of early post-implantation epiblast and are 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 distinct formative phase of pluripotency preparatory to lineage priming.
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge CB2 1QR, UK tk360@cam.ac.uk austin.smith@cscr.cam.ac.uk.
Tüzer
T
Kalkan
Babraham Institute, Cambridge CB22 3AT, UK.
Nelly
N
Olova
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge CB2 1QR, UK.
Mila
M
Roode
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge CB2 1QR, UK.
Carla
C
Mulas
Babraham Institute, Cambridge CB22 3AT, UK.|Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Heather J
HJ
Lee
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge CB2 1QR, UK.
Isabelle
I
Nett
Radboud University, Faculty of Science, Department of Molecular Biology, Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen 6500HB, The Netherlands.
Hendrik
H
Marks
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge CB2 1QR, UK.|Babraham Institute, Cambridge CB22 3AT, UK.
Rachael
R
Walker
Radboud University, Faculty of Science, Department of Molecular Biology, Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen 6500HB, The Netherlands.
Hendrik G
HG
Stunnenberg
Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.|The Cambridge Centre for Proteomics, Cambridge System Biology Centre, University of Cambridge, Cambridge CB2 1QR, UK.
Kathryn S
KS
Lilley
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge CB2 1QR, UK.|Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 4BG, UK.
Jennifer
J
Nichols
Babraham Institute, Cambridge CB22 3AT, UK.|Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.|Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK.
Wolf
W
Reik
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge CB2 1QR, UK.
Paul
P
Bertone
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge CB2 1QR, UK tk360@cam.ac.uk austin.smith@cscr.cam.ac.uk.|Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.
Austin
0000-0002-3029-4682
A
Smith
D000818:Animals; D019070:Cell Lineage; D000066673:Cell Self Renewal; D058948:Cell Tracking; D019175:DNA Methylation / Q000235:genetics; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D017930:Genes, Reporter; D005855:Germ Layers / Q000166:cytology; D007700:Kinetics; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D033581:Stem Cell Transplantation; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D014157:Transcription Factors
ES cells; Epiblast; Methylome; Pluripotency; Rex1; Transcriptome