Active DNA demethylation in human postmitotic cells correlates with activating histone modifications, but not transcription levels

We explored this epigenetic phenomenon in a natural setting of post-mitotic cells: the differentiation of human peripheral blood monocytes into macrophages or dendritic cells, which proceeds without cell division. Using a global, comparative CpG methylation profiling approach, we identified many novel examples of active DNA demethylation and characterized accompanying transcriptional and epigenetic events at these sites during monocytic differentiation. We show that active DNA demethylation is not restricted to proximal promoters and that the time-course of demethylation varies for individual CpGs. Irrespective of their location, the removal of methylated cytosines always coincided with the appearance of activating histone marks.Demethylation events are highly reproducible in monocyte-derived dendritic cells from different individuals. Our data suggest that active DNA demethylation is a precisely targeted event that parallels or follows the modification of histones, but is not necessarily coupled to alterations in transcriptional activity.The methylation of cytosine in the context of CpG dinucleotides in mammalian DNA is generally associated with gene silencing. The controlled setting and removal of DNA methylation are crucial for proper execution of essential regulatory programs in embryonic development, X-chromosome inactivation, parental imprinting as well as cellular differentiation [1-4]. Altered levels of cytosine methylation are associated with various diseases and may promote neoplastic development [5,6].Whereas the process of DNA methylation, which is catalyzed by a group of DNA methyltransferases (DNMTs) is well characterized [7,8], the mechanisms responsible for the removal of methylated cytosines are less well understood. The failure of maintenance DNMTs to methylate a newly synthesized daughter strand during cell cycle progression represents a non-enzymatic, passive way of erasing the 5-methylcytosine mark that requires at least two cycles of replicatio