Fig. 1: Generation of germline-specific epigenome-edited mice.

a In mice and humans, under normal conditions, Igf2 is expressed from the sperm-derived paternal allele (P), while H19 is expressed from the oocyte-derived maternal allele (M). In patients with Silver-Russell syndrome, DNA demethylation in H19-DMR results in biallelic expression of H19 and repression of Igf2, leading to fetal intrauterine growth retardation. Closed circles indicate methylated CpGs and open circles indicate unmethylated CpGs. b Schematic representation of germline-specific epigenome-edited mice. In WT male mice, H19-DMR sites are progressively hypermethylated until the pro-spermatogonia stage by an endogenous de novo methylation mechanism (left), while this region is demethylated during spermatogenesis in germline-specific epigenome-edited mice (right). This system can reveal whether an epimutation introduced in sperm is transmitted to the next F1 generation, leading to phenotypic changes.