Abstract
We characterized the landscape of DNA methylation (DNAm) across the first two decades of human neocortical development in neurons and glia using whole-genome bisulfite sequencing. We show that the rate of DNAm changes more dramatically during the first five years of postnatal life than during the entire remaining period. We further refined global patterns of increasingly divergent neuronal CpG and CpH methylation (mCpG and mCpH) into six unique developmental trajectories, within which neighboring mC levels—independent of sequence context—were highly correlated, unlike across the genome, where mCpG levels were correlated but mCpH levels were not. We then integrated paired RNA-seq data and identified direct regulation of hundreds of transcripts and their splicing events exclusively by mCpH, independent of mCpG levels, across this period of human cortical development. In addition to expanding the relationship between mCpH and gene expression, these splicing-associated cytosines and developmentally dynamic DNAm regions were associated with neuropsychiatric disease risk sequence, providing insight into the cell type and timing of dynamic epigenomic remodeling in known disease risk genes and loci.
Significance Statement By studying DNA methylation levels within neurons and glia across human neocortical development, we show that the first five years of life is a critical period of epigenetic plasticity, identify a novel role of CpH methylation in gene expression and splicing during neuronal maturation and parlay a clearer picture of methylation remodeling into better understanding of the cell type and timing of neuropsychiatric disease risk sequence activity.
