Abstract 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 were identified in the six datasets; approximately 38% of the cGCPs were positively correlated. The majority (&gt;90%) of cGCPs were tissue- or development-specific. We also observed that the correlation direction can be opposite in different tissues and ages. Further analysis highlighted the importance of cGCPs for their cellular functions and potential roles in complex traits and human diseases. For instance, 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 catalog of cGCPs compiled can be used to guide functional interpretation of genetic and epigenetic studies.

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