Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene

Maintenance of genomic methylation patterns in mammalian somatic cells depe nds on DNA methyltransferase-1 (Dnmt1). Mouse oocytes and preimplantation e mbryos lack Dnmt1 but express a variant of this protein called Dnmt1o. We e liminated Dnmt1o by deletion of the oocyte-specific promoter and first exon from the Dnmt1 locus. Homozygous animals were normal, but most heterozygou s fetuses of homozygous females died during the last third of gestation. Al though genomic methylation patterns were established normally in Dnmt1o-def icient oocytes, embryos derived from such oocytes showed a loss of allele-s pecific expression and methylation at certain imprinted loci. Transient nuc lear localization of Dnmt1o in 8-cell embryos suggests that this variant of Dnmt1 provides maintenance methyltransferase activity specifically at impr inted loci during the fourth embryonic S phase.