Haploinsufficiency, but not defective paternal 5mC oxidation, accounts for the developmental defects of maternal Tet3 knockouts

Cell Rep. 2015 Feb 3;10(4):463-70. doi: 10.1016/j.celrep.2014.12.049. Epub 2015 Jan 29.


Paternal DNA demethylation in mammalian zygotes is achieved through Tet3-mediated iterative oxidation of 5-methylcytosine (5mC) coupled with replication-dependent dilution. Tet3-mediated paternal DNA demethylation is believed to play important roles in mouse development given that Tet3 heterozygous embryos derived from Tet3-deficient oocytes exhibit embryonic sublethality. Here, we demonstrate that the sublethality phenotype of the Tet3 maternal knockout mice is caused by haploinsufficiency but not defective paternal 5mC oxidation. We found that Tet3 heterozygous progenies derived from heterozygous father or mother also exhibit sublethality. Importantly, wild-type embryos reconstituted with paternal pronuclei that bypassed 5mC oxidation develop and grow to adulthood normally. Genome-scale DNA methylation analysis demonstrated that hypermethylation in maternal Tet3 knockout embryos is largely diminished by the blastocyst stage. Our study thus reveals that Tet3-mediated paternal 5mC oxidation is dispensable for mouse development and suggests the existence of a compensatory mechanism for defective 5mC oxidation in preimplantation embryos.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / metabolism*
  • Animals
  • Blastocyst / metabolism
  • DNA Methylation / genetics
  • DNA Methylation / physiology
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / metabolism*
  • Dioxygenases
  • Female
  • Haploinsufficiency / genetics
  • Haploinsufficiency / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Oxidation-Reduction
  • Pregnancy
  • Proto-Oncogene Proteins / deficiency*
  • Proto-Oncogene Proteins / metabolism*
  • Zygote / metabolism


  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • 5-Methylcytosine
  • Dioxygenases
  • Tet3 protein, mouse

Associated data

  • GEO/GSE62719