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Lab, EMBL Romehttps://www.ebi.ac.uk/ena/browser/view/PRJNA612196Mus musculusxref:PubMed:32572256Early mammalian development entails widespread epigenome remodeling, including DNA methylation erasure and reacquisition, which facilitates developmental competence. To uncover the mechanisms that orchestrate global and focal DNA methylation (DNAme) dynamics, we coupled a single-cell ratiometric DNAme reporter with unbiased CRISPR screening. We identify key genes and regulatory pathways that drive developmental DNA hypomethylation, and characterise roles for Cop1 and Dusp6. We also identify Dppa2 and Dppa4 as essential safeguards of focal epigenetic states during (re)programming phases. In their absence, developmental genes and evolutionary young LINE1 elements lose H3K4me3 and gain ectopic de novo DNA methylation. Consequently, lineage-associated genes (and LINE1) acquire a repressive epigenetic memory in pluripotent cells, which renders them incompetent for activation during future lineage-specification. Dppa2/4 thereby sculpt a permissive epigenome for development by targeting H3K4me3 to counteract de novo methylation during (re)programming a function that has been co-opted by evolutionary young LINE1 to evade epigenetic decommissioning. Overall design: Examination of Dppa2, H3K4me3, H3K27me3 and H3K9me3 genome localisation in WT, Dppa2 KO and Dppa4 KO in ESC and EpiLC using Cut and RunENAfalseDppa2/4 Counteract De Novo Methylation to Establish a Permissive Epigenome for Development [Cut&Run]Dppa2/4 Counteract De Novo Methylation to Establish a Permissive Epigenome for Development [Cut&Run]2025-09-242020-05-31PRJNA612196GSE1468601009032572256