Lineage-specific and gestational age-dependent DNA methylation programming orchestrates human placental development.

Researchers built a single-base-resolution DNA methylation atlas of human placental trophoblasts across gestational ages. A lineage-specific methylation program is established immediately after implantation, and methylation then accumulates with gestational age. The program acts as a developmental barrier coordinating placental maturation and immune homeostasis. Integrating histone modifications and functional perturbations shows H3K27me3 and DNA methylation change in sequence and silence proinflammatory loci, while repeat elements switch from H3K9me3 to DNA methylation to maintain genome stability.