Genome-Scale Oscillations in DNA Methylation during Exit from Pluripotency

Steffen Rulands, Heather J. Lee, Stephen J. Clark, Christof Angermueller, Sébastien A. Smallwood, Felix Krueger, Hisham Mohammed, Wendy Dean, Jennifer Nichols, Peter Rugg-Gunn, Gavin Kelsey, Oliver Stegle, Benjamin D. Simons, Wolf Reik

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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. Exit from pluripotency and priming for differentiation into somatic lineages are associated with genome-wide de novo DNA methylation. We show that during this phase, co-expression of DNMT3 and TET enzymes promotes coherent, genome-scale oscillations in DNA methylation in vitro and in vivo. These oscillations are paralleled by oscillations in short-lived transcripts.

Original languageEnglish (US)
Pages (from-to)63-76.e12
JournalCell Systems
Volume7
Issue number1
DOIs
StatePublished - Jul 25 2018
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

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