Epigenetic modification of chromatin, including DNA methylation at the sites of CpG dinucleotides, is a key regulator of gene expression, growth and differentiation in virtually all tissues, including brain. Dysregulated DNA methylation, or methyl-CpG-dependent chromatin remodeling, is thought to underlie ICF syndrome, Rett��s disorder and other mental retardation syndromes. Furthermore, changes in methylation status at selected genomic loci may affect social cognition, learning and memory and stress-related behaviors and is believed to contribute to dysregulated gene expression in a range of adultonset neuropsychiatric disorders, including autism, schizophrenia, depression and Alzheimer��s disease. Finally, there is strong evidence that aberrant methylation of tumor suppressor genes contributes to the molecular pathology of a subset of astrogliomas and other types of brain cancers. However, despite its clinical importance, the regulation of DNA cytosine methylation, particularly in the human brain, remains poorly understood. To date, there are no comprehensive studies which have monitored methylation at multiple loci during the course of brain development and aging, or in chronic psychiatric disease. Furthermore, all previous studies of DNA methylation in human or animal brain utilized tissue homogenates comprised of a highly heterogeneous mixture of neurons and glia, or examined DNA methylation in subfractions of chromatin defined by site-specific EX 527 histone modifications and therefore it remains to be determined whether or not DNA methylation is MK-0683 149647-78-9 dynamically regulated in terminally differentiated neurons. Given this background, the present study was undertaken to provide a first insight into the dynamics of DNA methylation in the human cerebral cortex. Altogether, we examined 50 loci, mostly CpG islands within the 59 end of genes, during the course of development, maturation and aging. Additionally, we assessed the methylation status for these same loci in Alzheimer��s disease and schizophrenia; the former condition is characterized by chronic neurodegeneration and the latter by widespread transcriptional and metabolic perturbations in the absence of large scale loss of neurons. While disease-associated alterations were limited to 2/50 sequences in the Alzheimer��s cohort of the present study, the majority of genomic loci, including genes implicated in neural development and CNS tumors, showed a striking age-associated increase in methylated CpGs. Furthermore, we show that DNA methylation is dynamically regulated in differentiated neurons during the transition from childhood to advanced age. Collectively, our results suggest that DNA methylation in the human cerebral cortex, including its neuronal constituents, is dynamically regulated across the full lifespan and potentially affects a substantial portion of the genome.