Third, we asked whether tissue environment or developmental origin is the primary driving factor in DNA methylation differences observed in more differentiated cell types55, using epigenomes from skin cell types (keratinocytes E057/058, melanocytes E059/E061, and fibroblasts E055/056) that share a common tissue environment but possess distinct embryonic origins (surface ectoderm, neural crest, and mesoderm, respectively). We found that despite the shared tissue environment, these three cell types displayed lower overlap in their DNA methylation and histone modification signatures, and instead were more similar to other cell types with a shared developmental origin. Using a set of DMRs (Table S4e) defined specifically in the skin cell types55, keratinocytes shared 1392 (18%) of DMRs with surface ectoderm-derived breast cell types (Hypergeometric P-value<10−6), and 97% of these were hypomethylated. These shared DMRs were enriched for regulatory elements and cell-type relevant genes, suggesting a common gene regulatory network and shared signaling pathways and structural components55. These results suggest that common developmental origin can be a primary determinant of global DNA methylation patterns, and sometimes supersedes the immediate tissue environment in which they are found.
