Description

Genome scale oscillations of DNA methylation during exit from pluripotency

Heather J Lee^1,2*, Steffen Rulands^3,4,5,6,7*, Stephen J Clark¹, Christof Angermueller⁷, Sébastien A Smallwood^1,9, Felix Krueger¹⁰, Hisham Mohammed¹, Wendy Dean¹, Jennifer Nichols⁵, Peter Rugg-Gunn^1,5, Gavin Kelsey¹, Oliver Stegle⁸, Benjamin D Simons^3,4,5,# and Wolf Reik^1,2,5,7,11#

¹Epigenetics Programme, Babraham Institute, Cambridge, UK; ²Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; ³Cavendish Laboratory, Department of Physics, JJ Thomson Avenue, University of Cambridge, Cambridge CB3 0HE, UK; ⁴The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; ⁵Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, UK; ⁶Max Planck Institute for the Physics of Complex Systems, Nöthnitzer Str. 38, 01187 Dresden; ⁷Department of Physiology, Development and Neuroscience, University of Cambridge, UK; ⁸European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, UK; ⁹Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH 4058 Basel, Switzerland; ¹⁰Bioinformatics Group, Babraham Institute, Cambridge, UK; ¹¹Centre for Trophoblast Research, University of Cambridge, UK

*These authors contributed equally and are ordered alphabetically

^#These authors jointly directed this work

Pluripotency is associated with 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 accompanied by genome-wide de novo DNA methylation. During this phase, we find that the paradoxical co-expression of enzymes that promote methylation and demethylation, DNMT3s and TETs, promotes cell-to-cell variability in DNA methylation. Using a combination of single-cell sequencing and quantitative biophysical modelling, we show that these factors drive coherent, genome-scale and CpG density-dependent oscillations of DNA methylation. Analysis of parallel single-cell transcriptional and epigenetic profiling provides evidence for the same oscillatory dynamics in vivo. These observations provide fresh insights into the emergence of epigenetic heterogeneity during early embryo development, suggesting that dynamic changes in DNA methylation may assist in regulating early fate decisions.