EZHIP-mediated PRC2 inhibition is required to maintain H3K27me3-dependent imprinting post fertilization

Zygote inherits parental genomes with distinct chromatin structure. In eutherian mammals, this asymmetry is seen as crucial for embryonic development notably through its involvement in gene imprinting. Besides the well-established role of DNA methylation for gene imprinting, H3K27me3 has also been shown to mediate a transient form of imprinting in mice. Here, we show that maternal deletion of Ezhip, a negative regulator of PRC2, while increasing the asymmetric distribution of H3K27me3 among the parental genomes at the zygotic stage, in fine, impairs H3K27me3-dependent imprinting and mitigates X Chromosome Inactivation in pre-implantation embryos. We show that EZHIP protein, translated from the maternal pool of RNAs, is present during the first cell divisions post-fertilization. It limits PRC2 enzymatic, avoiding the flattening of H3K27me3 deposition throughout the genome and the equalization of H3K27me3 deposition on the two parental genomes. Our study reveals the necessary inhibition of PRC2 activity post-fertilization for proper development in mice. Overall design: Single cell/embryo RNA samples were prepared from wt and Ezhip matKO oocytes, 2C embryos, blastocysts, and E6.5 extraembryonic ectoderm to assess the impact of maternal depletion of Ezhip on the early stages of embryonic development.