H3K27me3-dependent imprinting and transcriptional regulation in early mouse embryos requires EZHIP-mediated restriction of PRC2 activity

Zygotes inherit parental genomes with distinct chromatin structures. In eutherian mammals, this asymmetry is considered crucial for embryonic development, notably because it enables genomic imprinting. Besides the well-established role of DNA methylation in this process, a transient form of imprinting in mice has been shown to rely instead on H3K27me3. Here, we show that maternal deletion of Ezhip, encoding a negative regulator of PRC2, initially increases the asymmetric distribution of H3K27me3 among the parental genomes at the zygotic stage but subsequently impairs H3K27me3-dependent imprinting and mitigates X-chromosome inactivation in pre-implantation embryos. We show that EZHIP protein, translated from the maternal mRNA pool, is present during the first cell divisions post-fertilization and limits PRC2 enzymatic activity. In its absence, the H3K27me3 landscape is both expanded and flattened, and the asymmetry between the two parental genomes is lost. Our study reveals the deleterious consequences on early embryonic development of unleashing PRC2 activity.