ABSTRACT

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.

摘要

DNA 甲基化 (DNAm) 是整个发育过程中基因表达的关键表观遗传调节剂。发育中的产前大脑是一个高度动态的组织，但我们对整个发育过程中表观遗传变异的关键驱动因素的理解是有限的。因此，我们使用全基因组亚硫酸氢盐测序评估了产前皮质中超过 3900 万个位点的基因组甲基化，并发现了甲基化水平在整个发育过程中动态变化的位点和区域。我们看到这些位点的 DNAm 与附近的基因表达相关，并且富含产前脑组织中的增强子染色质状态。此外，这些基因座富含与神经精神疾病相关的基因和与神经发生相关的基因。我们还发现在产前发育期间两性之间 DNAm 的常染色体差异，尽管这些具有不太明显的功能后果。我们最后证实，在这个关键时期的动态甲基化特别是 CpG 甲基化，通常具有低水平的 CpH 甲基化。我们的研究结果提供了对产前大脑发育的详细洞察，以及生命后期出现的精神特征发病机制的线索。