CpG methylation in neurons: message, memory, or mask?

The study of CpG methylation of genomic DNA in neurons has emerged from the shadow of cancer biology into a fundamental investigation of neuronal physiology. This advance began with the discovery that catalytic and receptor proteins related to the insertion and recognition of this chemical mark are robustly expressed in neurons. At the smallest scale of analysis is the methylation of a single cytosine base within a regulatory cognate sequence. This singular alteration in a nucleotide can profoundly modify transcription factor binding with a consequent effect on the primary 'transcript'. At the single promoter level, the methylation-demethylation of CpG islands and associated alterations in local chromatin assemblies creates a type of cellular 'memory' capable of long-term regulation of transcription particularly in stages of brain development, differentiation, and maturation. Finally, at the genome-wide scale, methylation studies from post-mortem brains suggest that CpG methylation may serve to cap the genome into active and inactive territories introducing a 'masking' function. This may facilitate rapid DNA-protein interactions by ambient transcriptional proteins onto actively networked gene promoters. Beyond this broad portrayal, there are vast gaps in our understanding of the pathway between neuronal activity and CpG methylation. These include the regulation in post-mitotic neurons of the executor proteins, such as the DNA methyltransferases, the elusive and putative demethylases, and the interactions with histone modifying enzymes.