Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 N Wolfe St, Ste 300, Baltimore, MD, 21205, USA.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine (JHSOM), Baltimore, MD, 21205, USA.
Genome Biol. 2019 Sep 26;20(1):196. doi: 10.1186/s13059-019-1805-1.
DNA methylation (DNAm) is a critical regulator of both development and cellular identity and shows unique patterns in neurons. To better characterize maturational changes in DNAm patterns in these cells, we profile the DNAm landscape at single-base resolution across the first two decades of human neocortical development in NeuN+ neurons using whole-genome bisulfite sequencing and compare them to non-neurons (primarily glia) and prenatal homogenate cortex.
We show that DNAm changes more dramatically during the first 5 years of postnatal life than during the entire remaining period. We further refine global patterns of increasingly divergent neuronal CpG and CpH methylation (mCpG and mCpH) into six developmental trajectories and find that in contrast to genome-wide patterns, neighboring mCpG and mCpH levels within these regions are highly correlated. We integrate paired RNA-seq data and identify putative regulation of hundreds of transcripts and their splicing events exclusively by mCpH levels, independently from mCpG levels, across this period. We finally explore the relationship between DNAm patterns and development of brain-related phenotypes and find enriched heritability for many phenotypes within identified DNAm features.
By profiling DNAm changes in NeuN-sorted neurons over the span of human cortical development, we identify novel, dynamic regions of DNAm that would be masked in homogenate DNAm data; expand on the relationship between CpG methylation, CpH methylation, and gene expression; and find enrichment particularly for neuropsychiatric diseases in genomic regions with cell type-specific, developmentally dynamic DNAm patterns.
DNA 甲基化（DNAm）是发育和细胞身份的关键调节剂，在神经元中表现出独特的模式。为了更好地描述这些细胞中 DNAm 模式的成熟变化，我们使用全基因组亚硫酸氢盐测序在 NeuN+神经元中以单碱基分辨率描绘了人类新皮质发育头两个十年的 DNAm 图谱，并将其与非神经元（主要是神经胶质）和产前匀浆皮质进行了比较。
我们表明，DNAm 在出生后 5 年内的变化比在剩余的整个时期更为剧烈。我们进一步将神经元 CpG 和 CpH 甲基化（mCpG 和 mCpH）的全球模式细化为六个发育轨迹，并发现与全基因组模式相比，这些区域内相邻的 mCpG 和 mCpH 水平高度相关。我们整合了配对的 RNA-seq 数据，并确定了数百个转录本及其剪接事件仅由 mCpH 水平（独立于 mCpG 水平）在这一时期进行的潜在调节。最后，我们探讨了 DNAm 模式与与大脑相关表型发育之间的关系，并发现许多表型在鉴定的 DNAm 特征中具有丰富的遗传性。
通过在人类皮质发育过程中对 NeuN 分选的神经元中的 DNAm 变化进行分析，我们确定了新型、动态的 DNAm 区域，这些区域在匀浆 DNAm 数据中会被掩盖；扩展了 CpG 甲基化、CpH 甲基化和基因表达之间的关系；并在具有细胞类型特异性、发育动态 DNAm 模式的基因组区域中发现了神经精神疾病的富集。
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