Polycomb protein SCML2 mediates paternal epigenetic inheritance through sperm chromatin

Sperm chromatin retains small amounts of histones, and the chromatin states of sperm mirror gene expression programs of the next generation. It remains largely unknown how paternal epigenetic information is transmitted through sperm chromatin. Here we developed a novel mouse model of paternal epigenetic inheritance in which deposition of Polycomb repressive complex 2 (PRC2) mediated-repressive H3K27me3 is attenuated in the paternal germline. By applying modified methods of assisted reproductive technology, we rescued infertility of mice absent of Polycomb protein SCML2, which is the regulator of germline gene expression through the establishment of H3K27me3 on bivalent promoters with other active marks H3K4me2/3. In F1 males of Scml2-knockout mice, which has wild-type genotype, gene expression is dysregulated in the male germline during spermiogenesis. These dysregulated genes are targets of SCML2-mediated H3K27me3 in mature sperm. Thus, SCML2 mediates intergenerational inheritance of paternal epigenetic information through the regulation of sperm chromatin. RNA-seq analysis of livers and spermatozoa from Ctrl-F1, Scml2-KO-F1 and Scml2-KO-F2 male mice. Native ChIP-seq analysis for H3K27me3 and H3K4me3 in testicular and cauda-epididymal sperm from Crtl and Scml2-KO male mice.