Epigenetic gene regulation in the germline

生物学中最大的谜团之一是关于生命是如何永续存在的，并将继续 世世代代永垂不朽。哺乳动物生殖系的一个关键特征是 它的性别二型性：精子发生和卵子发生。这些二态发育 流程本质上是复杂的，这种复杂性对 了解生命的永恒性和各种生殖系衍生的治疗方法的发展 遗传性和表观遗传性疾病。因此，在R35的应用中，我们的研究方向是一致的 要回答以下问题：表观遗传机制如何管理不同的性别 精子发生和卵子发生中的二态过程，最终产生功能性的 精子和卵子？自从我十年前独立以来，我和我的团队一直在努力构建 控制哺乳动物精子发生的表观遗传机制的详细图景。我们 已经表明，生殖细胞发育中从有丝分裂到减数分裂的转变不仅是值得注意的 基因表达的全球变化，但表观基因组的动态重组；简而言之，我们 揭示了减数分裂本身是一个全球表观基因组重编程的过程。我的研究 该计划开创了这些概念，并开发了破译生殖系的创新方法 为下一代做好准备的关键机制，为未来奠定坚实的基础 研究。 为了理解关键的性二态过程，我们把重点放在 精子发生和卵子发生的过程。在精子发生过程中，出生后的生殖细胞进入干细胞 细胞阶段，经历减数分裂，并维持长期的精子生产。我们将澄清 从干细胞阶段到精子发生的全球表观遗传学机制 生产，重点是表观遗传机制和它们的动态变化 对下一代的重要性。因为，在男性减数分裂中，性染色体失活(MSCI) 作为关键的性二态过程，我们还将确定 DNA损伤反应通路--引导MSCL--在性染色体的表观遗传调控中。 相比之下，雌性生殖细胞在胚胎中经历减数分裂，并进入延长的 减数分裂停滞--人类持续数十年--在卵母细胞成熟之前。我们将决定 卵子发生关键阶段的表观遗传机制补充我们的研究 雄性生殖细胞。最终，我们将揭示不同的特点和统一的原则 精子发生和卵子发生。综上所述，我们处于独特的地位，可以澄清 基本生殖系机制如何相交以确保基因组维护、基因组防御和 系统水平上的表观遗传基因调控。提出了本文的研究方向。 应用程序具有内聚性和协同性，具有支持研究的高潜力 人类生殖系生物学的重大、变革性进展 生殖，以及生殖健康。

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: spermatogenesis 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 govern distinct sexually dimorphic processes in spermatogenesis and oogenesis, culminating in the generation 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 spermatogenesis. 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 spermatogenesis 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, meiotic sex chromosome inactivation (MSCI) functions as a key sexually dimorphic process, we will also determine the molecular functions of DNA damage response pathways-which direct MSCl-in the epigenetic 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 advances in germline biology, human reproduction, and reproductive health in general.