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Fig. 7 Inherited methylome coupled by enhancer dememorization resets an epigenetic gate that safeguards embryonic programs.(A) Maternal Dnmt1–mediated inherited global DNA methylome coupled with enhancer dememorization plays an instrumental role in restoring a full methylome to ultimately safeguard embryonic development against premature activation of adult programs. In WT embryos, inherited methylome sets up an EpiGate after fertilization and effectively repress adult enhancers, which are preferentially CG-rich. Embryonic enhancers, which are CG-poor, and insensitive to DNA methylation, can function while hypermethylated, and instruct embryonic transcription program. At the phylotypic stage, expression of tet genes demethylates CG-rich adult enhancers, allowing their activation and cell lineage differentiation. While in maternal dnmt1 mKD embryos, inherited DNA methylome failed to be maintained after fertilization, hence destroying the EpiGate. This leads to aberrant activation of adult programs in early embryos, accompanied by developmental failure and embryonic lethality around gastrulation. (B) Enhancer dememorization resets the developmental clock by restoring a ground-state (green shade) free of parental epigenetic memories in both mammals (blue, human and mouse) and nonmammalian vertebrate (red, zebrafish) around blastula stage. This epigenetic resetting is achieved through global DNA remethylation and demethylation in mammals and through enhancer hypermethylation in zebrafish. Embryonic enhancers are then demethylated in gastrula only in mammals, where TETs are expressed, but not in zebrafish, where TETs are still silenced. Zebrafish embryonic enhancers are nevertheless functioning presumably due to their low CG densities and insensitivity to DNA methylation. Adult enhancers are subsequently demethylated by TETs in both mammals and zebrafish. In mammals, embryonic enhancers also remain hypomethylated in adult tissues despite being decommissioned (11, 12).