Dynamic methylome remodeling throughout mammalian fetal development

Genetic studies have revealed an essential role for cytosine DNA methylation in gene regulation. However, its spatiotemporal distribution in the developing embryo remains obscure. Here, we profiled the DNA methylation landscape of 12 mouse tissues/organs at 8 developmental stages spanning from early embryo to birth. In-depth analysis of such spatiotemporal epigenome maps uncovered widespread regulatory DNA element dynamics during embryogenesis. We systematically delineated methylation variants that likely drive gene transcription, whose human counterparts are enriched for genetic risk factors of human diseases. Strikingly, these predicted regulatory elements predominantly lose CG methylation during fetal development, whereas the trend is reversed after birth. Key transcription factors, essential for early tissue/organ development, accumulate non-CG methylation within their gene bodies, coinciding with transcriptional repression during late stage fetal development. These spatiotemporal epigenomic datasets provide a valuable resource for studies of gene regulation during mammalian tissue/organ progression and the possible origins of human developmental diseases. RNA-seq data (in replicate) of forebrain, midbrain, hindbrain and liver in mouse embryos from embryonic day 10.5 (E10.5) to postnatal day 0 (P0)遗传学研究已揭示胞嘧啶DNA甲基化（cytosine DNA methylation）在基因调控中发挥核心作用。然而，其在发育胚胎中的时空分布特征仍不明确。本研究对从早期胚胎至出生阶段的8个发育时期内的12种小鼠组织/器官的DNA甲基化图谱进行了系统性分析。通过对这些时空表观基因组图谱的深入解析，我们揭示了胚胎发生过程中调控性DNA元件的广泛动态变化。我们系统描绘了可能驱动基因转录的甲基化变异位点，其人类同源区域显著富集人类疾病的遗传风险因子。值得注意的是，这些预测得到的调控元件在胎儿发育阶段主要丢失CG甲基化（CG methylation），而该趋势在出生后发生逆转。对早期组织/器官发育至关重要的关键转录因子，其基因本体区域会积累非CG甲基化（non-CG methylation），这一现象与胎儿发育晚期的转录抑制过程相契合。本研究产生的这套时空表观基因组数据集，为哺乳动物组织/器官发育过程中的基因调控研究，以及人类发育性疾病的潜在发病机制探索提供了宝贵的研究资源。此外还包含小鼠胚胎于胚胎第10.5天（E10.5）至出生后第0天（P0）期间，前脑、中脑、后脑及肝脏的重复RNA测序（RNA-seq）数据。