Principles governing DNA methylation during neural lineage and subtype specification

DNA methylation, in concert with other epigenetic regulators, controls the accessibility of transcription factors to DNA. While comprehensively described in the development of neuronal progenitors, the role of DNA methylation/demethylation in neuronal lineage/subtype specification is not known. By profiling two distinct neuronal lineages, and five neuron subtypes in the hippocampus and striatum, we uncovered a set of five principles that govern DNA methylation dynamics in neurodevelopment. By dividing neurodevelopment to three alternating methylation and demethylation periods and applying the principles to each of these stages, we created a matrix that comprehensively describes the targets, genomic contexts, functional consequences and putative mechanisms of methylation/demethylation events. The overarching theme is that the developmental methylation program is remarkably similar in the hippocampal and striatal lineages, with significant divergence only occurring during subtype specification. Our matrix can be cross-referenced with disease-associated epigenetic changes to specify the possible events and underlying principles compromised in disease. Compared tissue from C57BL6 male animals at differenent developmental timepoints and regions for differences in DNA methylation and RNA expression. Additionally Dnmt3a conditional knockdown mice were used to determine role of Dnmt3a during development.