The DNA methyltransferases of mammals

The biological significance of 5-methylcytosine was in doubt for many years , but is no longer, Through targeted mutagenesis in mice it has been learnt that every protein shown by biochemical tests to be involved in the establ ishment, maintenance or interpretation of genomic methylation patterns is e ncoded by an essential gene. A human genetic disorder (ICF syndrome) has re cently been shown to be caused by mutations in the DNA methyltransferase 3B (DNMT3B) gene, A second human disorder (Rett syndrome) has been found to r esult from mutations in the MECP2 gene, which encodes a protein that binds to methylated DNA. Global genome demethylation caused by targeted mutations in the DNA methyltransferase-l (Dnmt1) gene has shown that cytosine methyl ation plays essential roles in X-inactivation, genomic imprinting and genom e. stabilization. The majority of genomic 5-methylcytosine is now known to enforce the transcriptional silence of the enormous burden of transposons a nd retroviruses that have accumulated in the mammalian genome. It has also become clear that programmed changes in methylation patterns are less impor tant in the regulation of mammalian development than was previously believe d. Although a number of outstanding questions have yet to be answered (one of these questions involves the nature of the cues that designate sites for methylation at particular stages of gametogenesis and early development), studies of DNA methyltransferases are likely to provide further insights in to the biological functions of genomic methylation patterns.