Project description:Determining the mechanisms that establish and regulate the transmission of non-genetic (i.e. epigenetic) information from parent to offspring is critical for understanding disease heredity. Using an innovative model to assess transmission of epigenetic effects, we provide evidence that Polycomb Repressive Complex 2 (PRC2) mediates inheritance through the male germline. This study reveals a novel role for histone modifying complexes in epigenetic inheritance, with important implications for understanding disease inheritance.
Project description:Determining the mechanisms that establish and regulate the transmission of non-genetic (i.e. epigenetic) information from parent to offspring is critical for understanding disease heredity. Using an innovative model to assess transmission of epigenetic effects, we provide evidence that Polycomb Repressive Complex 2 (PRC2) mediates inheritance through the male germline. This study reveals a novel role for histone modifying complexes in epigenetic inheritance, with important implications for understanding disease inheritance.
Project description: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.
Project description:Background: Defining the mechanisms that establish and regulate the transmission of epigenetic information from parent to offspring is critical for understanding disease heredity. Currently, the molecular pathways that regulate epigenetic information in the germline and its transmission to offspring are poorly understood. Results: Here we provide evidence that Polycomb Repressive Complex 2 (PRC2) regulates paternal inheritance, both at the phenotypic and molecular levels. Reduced PRC2 function in mice resulted in male sub-fertility and altered epigenetic and transcriptional control of retrotransposed elements in fetal male germ cells. Males with reduced PRC2 function produced offspring that over-expressed retrotransposed pseudogenes and had altered preimplantation embryo cleavage rates and cell cycle control. Conclusion: This study reveals a novel role for the histone modifying complex, PRC2, in epigenetic inheritance, with important implications for understanding disease inheritance.
Project description:Transgenerational epigenetic inheritance (TEI) describes the transmission of gene-regulatory information across generations without altering DNA sequences. TEI allows priming of offspring towards changing environmental conditions and plays a role in the maintenance of gene silencing of selfish genetic elements like transposons. Small regulatory RNAs are well known to act in TEI, and can be transmitted via the male. Such inheritance via sperm requires dedicated mechanisms, as much of the cellular content is extruded during spermatogenesis. We identify a phase separation-based mechanism, which couples the paternal inheritance of a specific small RNA-bound silencing factor via S-palmitoylation to the transport of membranous organelles. Our findings uncover a thus far unknown paternal TEI mechanism, and describe a novel mode of transport of phase-separated condensates.