The methylome of the human frontal cortex across development

Abstract

DNA methylation (DNAm) plays an important role in epigenetic regulation of gene expression, orchestrating tissue differentiation and development during all stages of mammalian life. This epigenetic control is especially important in the human brain, with extremely dynamic gene expression during fetal and infant life, and becomes progressively more stable at later periods of development. We characterized the epigenetic state of the developing and aging human frontal cortex in post-mortem tissue from 351 individuals across the lifespan using the Illumina 450k DNA methylation microarray. The largest changes in the methylome occur at birth at varying spatial resolutions - we identify 359,087 differentially methylated loci, which form 23,732 significant differentially methylated regions (DMRs). There were also 298 regions of long-range changes in DNAm, termed \"blocks\", associated with birth that strongly overlap previously published colon cancer \"blocks\". We then identify 55,439 DMRs associated with development and aging, of which 61.9% significantly associate with nearby gene expression levels. Lastly, we find enrichment of genomic loci of risk for schizophrenia and several other common diseases among these developmental DMRs. These data, integrated with existing genetic and transcriptomic data, create a rich genomic resource across brain development.