Controlled nuclear uptake of DNA methyltransferase and targeting to functional domains within the nucleus

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DNA methylation plays an important role in the regulation of gene expression and chromatin structure and is essential for normal mammalian development. We have elucidated the structure of the DNA methyltransferase gene (Dnmt1) and have identified various Dnmt1 isoforms. Following on our identification of a sequence targeting the enzyme to replication foci, we have identified and characterized another region that is responsible for cytoplasmic retention of the enzyme during early development. We want to screen for interacting factors that are involved in the developmentally controlled nuclear uptake of Dnmt1 and its association with nuclear replication foci. We have already introduced various Dnmt1 mutations in ES cells to study the mechanisms of this regulation. With this approach we also want to investigate the role of the controlled subcellular localization of Dnmt1 in the change of DNA methaylation patterns during early development and in the precise replication of epigenetic information in somatic cells.