Priming Epigenetic Landscape at Gene Promoters through Transcriptional Activation in Mammalian Germ Cells

In mammalian germ cells, a cycle of erasing and resetting epigenetic information is crucial for sex-specific gametogenesis and early embryogenesis. Specific chromatin states at promoters allow genes to be expressed at the appropriate time during germ cell development, however, the mechanism that establishes such characteristic chromatin states remains unclear. Here, we show that, in mouse male embryonic germ cells, promoters of developmental and housekeeping genes are selectively protected from de novo DNA methylation, coinciding with their transient upregulation and genome-wide erasure of H3K27me3. Importantly, a specific level of H3K4me3 density at the promoters serves as a potent probe that distinguishes between hypo- and hyper-DNA methylation states. Subsequent restoration of H3K27me3 contributes to establishing bivalent chromatin states that prime genes for activation at later developmental stages. These findings reveal a molecular framework shaping the epigenetic landscape at promoters with long-term effects beyond germ cell development.