PRC2?s histone H3 lysine-27 methylation activity plays a pivotal role in cellular homeostasis maintenance, cell lineage specification, and disease development through maintaining chromatin structure and transcriptional programs. Genome-wide H3K27 methylation is restored in daughter cells for cell identity maintenance during cell proliferation1 and are also transmitted into next generation through gametes for gene regulation in early embryogenesis2,3. The epigenetic memory of H3K27me landscapes is determined by the temporospatial control of PRC2 recruitment and assembly on targeting chromatin loci. The interaction between PRC2 and chromatin is mediated through a complicated process involving repressive transcriptional states, CpG-rich DNA elements, chromatin-binding proteins, DNA modifications, histone modifications, and noncoding RNAs4. This process is particularly important for mammalian spermatogenesis, which requires numerous epigenetic changes to accompany the transition from somatic, diploid precursors to mature, haploid gametes [reviewed5]. Faithful execution of the meiotic program requires that the genome undergoes large-scale changes to histone and DNA modifications as well as to chromatin structure, all of which require the action of a large number of chromatin modifying pathways6. Homologous recombination occurs during the first meiotic prophase. DNA double-strand breaks (DSBs) are induced, and repair at these breaks generates DNA recombination between homologous chromosomes. Many of the factors required for repair of stress-induced DNA damage in somatic cells function during male meiosis. In addition to their well-characterized roles in transcriptional regulation, chromatin-remodeling complexes also have roles in DNA repair7,8. Because male germ cell development is characterized by DSBs and dynamic changes to gene expression patterns, including a transition from somatic to germ-cell- specific genes, global repression of transposon activity, and meiotic sex chromosome inactivation5, it stands to reason that this process is particularly sensitive to the activity of several epigenetic regulators known to influence meiotic recombination. Proposed experiments will address the mechanisms by which PRC1/2 and SWI/SNF subunits regulate epigenetic memory during spermatogenesis, as well as defining how associations between complexes and lncRNAs shape the male epigenome during meiosis.
Spermatogenesis is a developmental cascade in which genetic information is passed on from mitotic precursors to meiotically derived haploid gametes. Male infertility can result from the incorrect interpretation of genome sequence due to abnormalities in the structure of chromatin that packages DNA in the nucleus (epigenetics). Studies on chromatin modifying proteins have demonstrated their ability to disrupt histone-DNA contacts and reposition nucleosomes. Consequently, these complexes are critical in regulating global gene expression. Genetic experiments that elucidate the biological specificity of these proteins, along with the abnormal outcomes associated with infertility when inappropriately expressed, ultimately may lead to targeted treatments.
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