Epigenetic targeting in the mouse zygote marks DNA for later methylation: a mechanism for maternal effects in development

The transgenic sequences in the mouse line TKZ751 are demethylated on a DBA/2 inbred strain background but become highly methylated at postimplantation stages in offspring of a cross with a BALB/c female. In the reciprocal cross the transgene remains demethylated suggesting that imprinted BALB/c methylation modifiers or egg cytoplasmic factors are responsible for this striking maternal effect on de novo methylation. Reciprocal pronuclear transplantation experiments were carried out to distinguish between these mechanisms. The results indicate that a maternally-derived oocyte cytoplasmic factor from BALB/c marks the TKZ751 sequences at fertilization; this mark and postzygotic BALB/c modifiers are both required for de novo methylation of the target sequences at postimplantation stages. Using genetic linkage analyses we mapped the maternal effect to a locus on chromosome 17. Moreover, seven postzygotic modifier loci were identified that increase the postimplantation level of methylation. Analysis of interactions between the maternal and the postzygotic loci shows that both are needed for de novo methylation in the offspring. The combined experiments thus reveal a novel epigenetic marking process at fertilization which targets DNA for later methylation in the foetus. The most significant consequence is that the genotype of the mother can influence the epigenotype of the offspring by this marking process. A number of parental and imprinting effects may be explained by this epigenetic marking.