DNA demethylase is a processive enzyme

DNA methylation patterns are generated during development by a sequence of methylation and demethylation events. We have recently demonstrated that ma mmals bear a bona fide demethylase enzyme that removes methyl groups from m ethylated cytosines. A general genome wide demethylation occurs early in de velopment and in differentiating cell lines. This manuscript tests the hypo thesis that the demethylase enzyme is a processive enzyme. Using bisulfite mapping, this report demonstrates that demethylase is a processive enzyme a nd that the rate limiting step in demethylation is the initiation of demeth ylation. Initiation of demethylation is determined by the properties of the sequence. Once initiated, demethylation progresses processively. We sugges t that these data provide a molecular explanation for global hypomethylatio n.