Reprogramming of DNA methylation patterns during mammalian preimplantation 
development involves the concurrent maintenance of methylation on differentially 
methylated domains (DMDs) of imprinted genes and a marked reduction of global 
(non-DMD) genomic methylation. In the developing mammalian embryo, one allele of 
a DMD is unmethylated, and the opposite parental allele is methylated, having 
inherited this methylation from the parental gamete. The maintenance of DMDs is 
important for monoallelic imprinted gene expression and normal development of 
the embryo. Because the DNMT1 cytosine methyltransferase governs maintenance 
methylation in mammals, rearrangements of non-DMD, but not DMD methylation in 
preimplantation embryos suggest that the preimplantation DNMT1-dependent 
maintenance mechanism specifically targets DMD sequences. We explored this 
possibility using an engineered mouse ES cell line to screen for mutant DNMT1 
proteins that protect against the loss of DMD and/or global (non-DMD) 
methylation in the absence of the wild-type endogenous DNMT1 methyltransferase. 
We identified DNMT1 mutants that were defective in maintenance of either DMD 
and/or non-DMD methylation. Among these, one mutant maintained non-DMD 
methylation but not imprinted DMD methylation and another mutant maintained just 
DMD methylation. The mutated amino acids of these mutants reside in a 
mammal-specific, disordered region near the amino terminus of DNMT1. These 
findings suggest that DNMT1 participates in epigenetic reprogramming through its 
ability to distinguish different categories of methylated sequences.