Epigenetic gene regulation in the germline

摘要 生物学中最大的谜团之一是关于生命是如何从 一代又一代。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。这些二态发育过程本质上是复杂的，这种复杂性构成了 理解生命的永恒性和各种疾病的治疗方法的发展面临重大挑战 由种系衍生的遗传病和表观遗传病。因此，在这个R35的应用中，我们的研究方向 共同解决以下问题：表观遗传机制如何控制不同的性别 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一个 控制哺乳动物精子发生的表观遗传机制的详细图景。我们已经证明了 生殖细胞发育中从有丝分裂到减数分裂的转变值得注意的不仅仅是基因的全球变化。 而是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种 全球表观基因组重编程的过程。我的研究项目开创了这些概念， 开发了创新的方法来解码对准备下一代至关重要的生殖系机制， 为未来的研究提供了严密的基础。 为了理解关键的性二态过程，我们关注的是 精子发生和卵子发生。在精子发生中，出生后的生殖细胞进入干细胞阶段，经历 减数分裂，并维持精子的长期生产。我们将阐明全球表观遗传机制 从干细胞阶段到精子产生的基本精子发生，重点是 表观遗传机制的动态变化及其对下一代的重要性。因为，在男性身上， 减数分裂性染色体失活(MSCI)作为关键的性二态过程，我们还将 确定引导MSCI的DNA损伤反应通路的分子功能 性染色体的表观遗传调节。相反，雌性生殖细胞在胚胎中经历减数分裂。 在卵母细胞成熟之前，进入减数分裂停滞的长期阶段--在人类中持续数十年。我们 将确定卵子发生关键阶段潜在的表观遗传机制，以补充我们的研究 雄性生殖细胞。最终，我们将揭示精子发生的不同特征和统一原则。 和卵子发生。综上所述，我们处于独特的地位，可以阐明基本的生殖系 确保基因组维护、基因组防御和表观遗传基因调控的机制相互交叉 系统层面。本申请中提出的研究方向是内聚性和协同性的，具有很高的 有潜力维持研究进展，并为生殖系生物学的重大、变革性进展提供信息； 人类生殖和生殖健康。

ABSTRACT 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 MSCI—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.