Epigenetic gene regulation in the germline

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Project Summary of parent grant R35 GM141085 One of the greatest mysteries in biology concerns how life has perpetuated, and continues to perpetuate, from generation to generation. A key feature of the mammalian germline is its sexual dimorphism: sper- matogenesis and oogenesis. These dimorphic developmental processes are inherently complex, and this complexity poses significant challenges to understanding the perpetuity of life and the development of treatments for various germline-derived genetic and epigenetic diseases. Thus, in this R35 application, our research directions converge to address the following question: How do epigenetic mechanisms gov- ern distinct sexually dimorphic processes in spermatogenesis and oogenesis, culminating in the genera- tion of functional sperm and eggs? Since I became independent ten years ago, I and my team have worked to construct a detailed picture of the epigenetic mechanisms that govern mammalian spermato- genesis. We have shown that the mitosis-to-meiosis transition in germ cell development is notable for not only global changes in gene expression but the dynamic reorganization of the epigenome; in brief, we have revealed that meiosis itself is a process of global epigenomic reprogramming. My research program has pioneered these concepts and developed innovative approaches to decode germline mechanisms crucial for preparing the next generation, providing a rigorous foundation for future research. To understand key sexually dimorphic processes, we focus on fundamental processes in sper- matogenesis and oogenesis. In spermatogenesis, postnatal germ cells enter a stem cell stage, undergo meiosis, and sustain long-term production of sperm. We will elucidate the global epigenetic mechanisms underlying spermatogenesis from the stem cell stage to sperm production, with an emphasis on dynamic changes in the epigenetic machinery and their importance to the next generation. Since, in males, mei- otic sex chromosome inactivation (MSCI) functions as a key sexually dimorphic process, we will also de- termine the molecular functions of DNA damage response pathways—which direct MSCI—in the epige- netic regulation of the sex chromosomes. In contrast, female germ cells undergo meiosis in embryos and enter a prolonged stage of meiotic arrest—spanning decades in humans—prior to oocyte maturation. We will determine epigenetic mechanisms underlying critical stages of oogenesis to complement our study of male germ cells. Ultimately, we will reveal distinct features and unifying principles of spermatogenesis and oogenesis. Taking all of this together, we are uniquely positioned to clarify how fundamental germline mechanisms intersect to ensure genome maintenance, genome defense, and epigenetic gene regulation on a systemic level. The research directions proposed in this application are cohesive and synergistic, with high potential to sustain research progress and inform significant, transformative ad- vances in germline biology, human reproduction, and reproductive health in general.