PLOS Genetics · 9 authors, 6 centres
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Amino-acid substitutions in the DNMT3A ADD domain in mice cause mosaic loss of CG methylation and near-complete loss of non-CG methylation in oocytes, leading to stochastic loss of maternal imprinting and embryonic lethality in mid-to-late gestation.
This study used a mouse model carrying amino-acid substitutions in the ADD domain of DNMT3A to investigate the role of the ADD-histone H3K4me0 interaction in de novo DNA methylation. Oocytes derived from homozygous females showed mosaic loss of CG methylation and almost complete loss of non-CG methylation. Embryos derived from these oocytes died in mid-to-late gestation, exhibiting stochastic and often all-or-none-type CG-methylation loss at imprinting control regions with misexpression of linked genes. The stochastic loss was shown to be a two-step process, with loss occurring in cleavage-stage embryos and regaining occurring after implantation. The authors propose that the ADD domain tethers DNMT3A to chromatin unmethylated at H3K4 and enables processive CG methylation.
