DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development

The establishment of DNA methylation patterns requires de novo methylation that occurs predominantly during early development and gametogenesis in mice. Here we demonstrate that two recently identified DNA methyltransferases, Dnmt3a and Dnmt3b, are essential for de novo methylation and for mouse development. inactivation of both genes by gene targeting blocks de novo methylation in ES cells and early embryos, but it has no effect on maintenance of imprinted methylation patterns. Dnmt3a and Dnmt3b also exhibit nonoverlapping functions in development, with Dnmt3b specifically required for methylation of centromeric minor satellite repeats. Mutations of human DNMT3B are found in ICF syndrome, a developmental defect characterized by hypomethylation of pericentromeric repeats. Our results indicate that both Dnmt3a and Dnmt3b function as de novo methyltransferases that play important roles in normal development and disease.

DNA甲基化模式的建立需要从头发育期间主要发生的甲基化和小鼠的配子发生。在这里，我们证明了两个最近确定的DNA甲基转移酶DNMT3A和DNMT3B对于从头甲基化和小鼠发育至关重要。通过基因靶向阻断ES细胞和早期胚胎的基因构成对两种基因的失活，但对维持印记甲基化模式没有影响。 DNMT3A和DNMT3B在发育中也表现出非重叠的功能，DNMT3B专门用于centromeric Minor卫星重复甲基化。人类DNMT3B的突变在ICF综合征中发现，这种发育缺陷为特征，其特征是周围粒粒体重复序列甲基化。我们的结果表明，DNMT3A和DNMT3B都起到了从头发育和疾病中重要作用的从头甲基转移酶。