Recent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive DNA demethylation in mammals

Nat Commun. 2020 Nov 24;11(1):5972. doi: 10.1038/s41467-020-19603-1.


Genome-wide DNA demethylation is a unique feature of mammalian development and naïve pluripotent stem cells. Here, we describe a recently evolved pathway in which global hypomethylation is achieved by the coupling of active and passive demethylation. TET activity is required, albeit indirectly, for global demethylation, which mostly occurs at sites devoid of TET binding. Instead, TET-mediated active demethylation is locus-specific and necessary for activating a subset of genes, including the naïve pluripotency and germline marker Dppa3 (Stella, Pgc7). DPPA3 in turn drives large-scale passive demethylation by directly binding and displacing UHRF1 from chromatin, thereby inhibiting maintenance DNA methylation. Although unique to mammals, we show that DPPA3 alone is capable of inducing global DNA demethylation in non-mammalian species (Xenopus and medaka) despite their evolutionary divergence from mammals more than 300 million years ago. Our findings suggest that the evolution of Dppa3 facilitated the emergence of global DNA demethylation in mammals.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biological Evolution
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Chromatin / metabolism*
  • Chromosomal Proteins, Non-Histone* / genetics
  • Chromosomal Proteins, Non-Histone* / metabolism
  • DNA Demethylation*
  • DNA Methylation
  • DNA-Directed DNA Polymerase / metabolism
  • Epigenomics
  • Evolution, Molecular
  • Gene Expression Regulation
  • Genes, Regulator
  • Germ Cells / metabolism
  • Mammals / genetics*
  • Mice
  • Pluripotent Stem Cells / metabolism*
  • Ubiquitin-Protein Ligases / metabolism


  • CCAAT-Enhancer-Binding Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • DPPA3 protein, human
  • Ubiquitin-Protein Ligases
  • Uhrf1 protein, mouse
  • Tet DNA polymerase
  • DNA-Directed DNA Polymerase