Max-Planck-Institute for Molecular Genetics
DNA-methylation plays an important role as an epigenetic signal in the regulation of imprinted genes. Differential methylation is thought to be established during gametogenesis and maintained during early embryogenesis despite of an extensive reprogramming of parental germ line methylation patterns. To understand possible mechanisms conferring maintenance of imprinted methylation we have investigated the fate of allele specific DNA methylation in the imprinted Igf2 and H19 genes. The global decrease of methylation during preimplantation development is thought to be achieved mainly by a passive mechanism, i.e. the lack of methylation maintenance during DNA replication. In contrast to this we observe that most of the methylation established in mature sperms in both genes is rapidly and largely erased by a process of active demethylation shortly after fertilization. This demethylation is apparently conferred by an active demethylase provided by the oocytoplasm. However, imprinting core elements, like the H19 upstream region, are apparently protected from this demethylation. In addition to this finding our results suggest a striking asymmetry in the epigenetic reprogramming of parental chromosomes during early cleavage stages. Whereby paternal chromosomes are actively and rapidly demethylated, maternal chromosomes are largely protected from this reaction during the first divisions and undergo demethylation at later cleavage stage most possibly by passive demethylation. The implications of our results on the setting and maintenance of parent of origin specific methylation patterns in imprinted genes will be discussed.