Characterizing the dynamic and functional DNA methylation landscape in the developing human cortex

DNA methylation (DNAm) is a key epigenetic regulator of gene expression across development. The developing prenatal brain is a highly dynamic tissue, but our understanding of key drivers of epigenetic variability across development is limited. We, therefore, assessed genomic methylation at over 39 million sites in the prenatal cortex using whole-genome bisulfite sequencing and found loci and regions in which methylation levels are dynamic across development. We saw that DNAm at these loci was associated with nearby gene expression and enriched for enhancer chromatin states in prenatal brain tissue. Additionally, these loci were enriched for genes associated with neuropsychiatric disorders and genes involved with neurogenesis. We also found autosomal differences in DNAm between the sexes during prenatal development, though these have less clear functional consequences. We lastly confirmed that the dynamic methylation at this critical period is specifically CpG methylation, with generally low levels of CpH methylation. Our findings provide detailed insight into prenatal brain development as well as clues to the pathogenesis of psychiatric traits seen later in life.

DNA甲基化（DNA methylation）是贯穿发育进程的基因表达关键表观遗传调控因子。发育中的产前大脑属于高度动态的组织，但目前学界对发育过程中表观遗传变异的关键驱动因素的认知仍较为有限。为此，我们采用全基因组亚硫酸氢盐测序（whole-genome bisulfite sequencing）技术，对产前大脑皮层中超过3900万个位点的基因组甲基化水平进行了检测，找到了在发育过程中甲基化水平呈动态变化的位点与区域。我们发现，这些位点的DNA甲基化水平与邻近基因的表达存在关联，且在产前大脑组织的增强子染色质状态中显著富集。此外，这些位点富集了与神经精神疾病相关的基因以及参与神经发生的基因。我们还在产前发育阶段发现了两性之间的常染色体DNA甲基化差异，不过此类差异的功能效应尚不明确。最后我们证实，这一关键时期的动态甲基化特指CpG甲基化，CpH甲基化的水平普遍较低。本研究结果为产前大脑发育提供了详尽的解析视角，也为日后生命阶段出现的精神疾病性状的发病机制提供了重要线索。