The genetic basis for DNA methylation variation across tissue and development

By analyzing genome-wide methylation patterns in multiple tissues from genetically distinct mouse strains, we identify thousands of differentially methylated regions (DMRs) linked to sequence variants. These DMRs reveal key factor-binding regulatory motifs that govern methylation programming, with ubiquitous DMRs established early in embryogenesis, whereas cell-type-specific DMRs emerge later during tissue differentiation.

Extending this approach to human data, we map over 21,000 methylation-associated SNPs, pinpointing genetic variants that regulate DNA methylation ubiquitously or in specific cell types. These findings highlight the role of transcription factor binding in shaping epigenetic landscapes and provide mechanistic insights to how genetic variation influences gene regulation and disease susceptibility. Our study establishes a systematic developmental framework for deciphering the genetic determinants of DNA methylation programming, offering a foundation for understanding epigenetics and phenotypic diversity with clinical implications in health and disease.