Spatiotemporal specificity of correlated DNA methylation and gene expression pairs across different human tissues and stages of brain development

DNA methylation (DNAm) that occurs on promoter regions is primarily considered to repress gene expression. Previous studies indicated that DNAm could also show positive correlations with gene expression. Both DNAm and gene expression profiles are known to be tissue- and development-specific. This study aims to investigate how DNAm and gene expression are coordinated across different human tissues and developmental stages, as well as the biological significance of such correlations. By analyzing 2,239 samples with both DNAm and gene expression data in the same human subjects obtained from six published datasets, we evaluated the correlations between gene and CpG pairs (GCPs) at cis-regions and compared significantly correlated GCPs (cGCPs) across different tissues and brains at different age groups. A total of 37,363 cGCPs was identified in the six datasets; approximately 38% of the cGCPs were positively correlated. The majority (>90%) of cGCPs was tissue- or development-specific. We also observed that the correlation direction can be opposite in different tissues and ages. Further analysis highlights the importance of cGCPs for their cellular functions and potential roles in complex traits and human diseases. For instance, the early developmental brain possessed a highly unique set of cGCPs that were associated with neurogenesis and psychiatric disorders. By assessing the epigenetic factors involved in cGCPs, we discovered novel regulatory mechanisms of positive cGCPs distinct from negative cGCPs, which were related to multiple factors, such as H3K27me3, CTCF, and JARD2. The catalogue of cGCPs compiled can be used to guide functional interpretation of genetic and epigenetic studies.

启动子区域上发生的DNA甲基化（DNA methylation, DNAm）通常被认为主要发挥基因表达抑制作用。既往研究表明，DNA甲基化也可与基因表达呈现正相关关联。已知DNA甲基化与基因表达谱均具有组织特异性和发育阶段特异性。本研究旨在探究不同人体组织与发育阶段中DNA甲基化与基因表达的协同调控模式，以及此类关联的生物学意义。本研究从6个已公开的数据集中获取了同一人类受试者的2239份同时包含DNA甲基化与基因表达数据的样本，通过分析这些样本，对顺式调控区域（cis-regions）内的基因-CpG对（gene and CpG pairs, GCPs）之间的关联进行了评估，并对比了不同组织以及不同年龄组大脑中显著关联基因-CpG对（significantly correlated GCPs, cGCPs）的分布特征。在6个数据集中共鉴定出37363个显著关联基因-CpG对，其中约38%呈正相关。绝大多数（>90%）的显著关联基因-CpG对具有组织特异性或发育阶段特异性。我们同时观察到，此类关联的方向在不同组织及年龄组中可呈现相反的情况。进一步分析凸显了显著关联基因-CpG对在细胞功能、复杂性状及人类疾病中潜在的重要作用。例如，发育早期的大脑拥有一套高度独特的显著关联基因-CpG对，这些关联对与神经发生及精神疾病密切相关。通过对显著关联基因-CpG对所涉及的表观遗传因子进行分析，我们发现了与负相关显著关联基因-CpG对不同的正相关关联对调控新机制，此类机制与H3K27me3、CTCF及JARD2等多种因子相关。本研究构建的显著关联基因-CpG对目录，可用于指导遗传与表观遗传研究中的功能注释与解读。