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Cell Syst. 2018 Jul 25;7(1):63-76.e12. doi: 10.1016/j.cels.2018.06.012.

Genome-Scale Oscillations in DNA Methylation during Exit from Pluripotency.

Author information

1
Cavendish Laboratory, Department of Physics, JJ Thomson Avenue, University of Cambridge, Cambridge CB3 0HE, UK; The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK; Max Planck Institute for the Physics of Complex Systems, Noethnitzer Str. 38, 01187 Dresden, Germany; Center for Systems Biology Dresden, Pfotenhauer Str. 108, 01307 Dresden, Germany. Electronic address: rulands@pks.mpg.de.
2
Epigenetics Programme, Babraham Institute, Cambridge, UK; Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW, Australia. Electronic address: heather.lee@newcastle.edu.au.
3
Epigenetics Programme, Babraham Institute, Cambridge, UK.
4
European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, UK.
5
Epigenetics Programme, Babraham Institute, Cambridge, UK; Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
6
Bioinformatics Group, Babraham Institute, Cambridge, UK.
7
Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.
8
Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK; Epigenetics Programme, Babraham Institute, Cambridge, UK.
9
Cavendish Laboratory, Department of Physics, JJ Thomson Avenue, University of Cambridge, Cambridge CB3 0HE, UK; The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK. Electronic address: bds10@cam.ac.uk.
10
Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK; Epigenetics Programme, Babraham Institute, Cambridge, UK; Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. Electronic address: wolf.reik@babraham.ac.uk.

Abstract

Pluripotency is accompanied by the erasure of parental epigenetic memory, with naïve pluripotent cells exhibiting global DNA hypomethylation both in vitro and in vivo. Exit from pluripotency and priming for differentiation into somatic lineages is associated with genome-wide de novo DNA methylation. We show that during this phase, co-expression of enzymes required for DNA methylation turnover, DNMT3s and TETs, promotes cell-to-cell variability in this epigenetic mark. Using a combination of single-cell sequencing and quantitative biophysical modeling, we show that this variability is associated with coherent, genome-scale oscillations in DNA methylation with an amplitude dependent on CpG density. Analysis of parallel single-cell transcriptional and epigenetic profiling provides evidence for oscillatory dynamics both in vitro and in vivo. These observations provide insights into the emergence of epigenetic heterogeneity during early embryo development, indicating that dynamic changes in DNA methylation might influence early cell fate decisions.

KEYWORDS:

DNA methylation; biophysical modeling; dynamics; embryo; epigenetic; pluripotency; stem cells

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