Naive pluripotency is associated with global DNA hypomethylation

Nat Struct Mol Biol. 2013 Mar;20(3):311-6. doi: 10.1038/nsmb.2510. Epub 2013 Feb 17.

Abstract

Naive pluripotent embryonic stem cells (ESCs) and embryonic germ cells (EGCs) are derived from the preimplantation epiblast and primordial germ cells (PGCs), respectively. We investigated whether differences exist between ESCs and EGCs, in view of their distinct developmental origins. PGCs are programmed to undergo global DNA demethylation; however, we find that EGCs and ESCs exhibit equivalent global DNA methylation levels. Inhibition of MEK and Gsk3b by 2i conditions leads to pronounced reduction in DNA methylation in both cell types. This is driven by Prdm14 and is associated with downregulation of Dnmt3a and Dnmt3b. However, genomic imprints are maintained in 2i, and we report derivation of EGCs with intact genomic imprints. Collectively, our findings establish that culture in 2i instills a naive pluripotent state with a distinctive epigenetic configuration that parallels molecular features observed in both the preimplantation epiblast and nascent PGCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Cell Differentiation
  • Cells, Cultured / drug effects
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation*
  • DNA-Binding Proteins
  • Diphenylamine / analogs & derivatives
  • Diphenylamine / pharmacology
  • Embryonic Stem Cells / physiology*
  • Enzyme Inhibitors / pharmacology
  • Epigenesis, Genetic
  • Gene Expression Profiling
  • Genomic Imprinting
  • Germ Cells / cytology*
  • Germ Cells / physiology
  • Germ Layers / cytology
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / physiology*
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • RNA-Binding Proteins
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptome

Substances

  • Benzamides
  • Chir 99021
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • PD 0325901
  • Prdm14 protein, mouse
  • Pyridines
  • Pyrimidines
  • RNA-Binding Proteins
  • Transcription Factors
  • Diphenylamine
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • DNA methyltransferase 3B
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • MAP Kinase Kinase Kinases
  • Glycogen Synthase Kinase 3

Associated data

  • GEO/GSE43398