DNA Methyltransferases Dnmt3a and Dnmt3b Are Essential for De Novo Methylation and Mammalian Development

We demonstrate that two recently identified DNA methyltransferases, Dnmt3a and Dnmt3b, are essential for de novo methylation and for mouse development

Masaki Okano; Daphne W Bell; Daniel A Haber; En Li

2004

Scholarcy highlights

  • Covalent modification of DNA by methylation of cytosine residues is a heritable and reversible epigenetic process, which is involved in regulation of a diverse range of biological processes in vertebrate animals, plants, and fungi
  • Inactivation of Both Dnmt3a and Dnmt3b Disrupts De Novo Methylation in ES Cells Since both Dnmt3a and Dnmt3b encode functional DNA methyltransferases with similar biochemical properties and both genes are expressed at high levels in ES cells, we speculated that Dnmt3a and Dnmt3b might have overlapping functions
  • Note that de novo methylation of proviral DNA was completely blocked in cells lacking both Dnmt3a and Dnmt3b
  • Dnmt3aϪ/Ϫ or Dnmt3bϪ/Ϫ single mutant ES cell lines methylate proviral DNA normally, the double mutant ES cells completely lacked de novo methylation activity. These results demonstrate that Dnmt3a and Dnmt3b are essential for de novo methylation in ES cells, and that these two gene products are redundant in this function
  • De Novo Methylation Is Impaired in Embryos To investigate whether the Dnmt3 mutant embryos are defective in de novo methylation, we examined global genomic methylation patterns in E9.5 Dnmt3aϪ/Ϫ, Dnmt3bϪ/Ϫ, and mutant embryos
  • Inactivation of both Dnmt3a and Dnmt3b disrupts de novo methylation of proviral DNA in ES cells and genome-wide de novo methylation occurring during early development, but it has no discernible effect on the maintenance of preexisting methylation patterns
  • Our results indicate that both Dnmt3a and Dnmt3b function as de novo methyltransferases that play important roles in normal development and disease

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