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延续的，并继续延续下去， 一代又一代哺乳动物生殖系的一个关键特征是其两性异形：精子发生 和卵子发生这些二态发育过程本身是复杂的，这种复杂性构成了 理解生命的永恒性和各种疾病治疗方法的发展面临的重大挑战 生殖系遗传和表观遗传疾病。因此，在R35应用中，我们的研究方向 聚集在一起解决以下问题：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，我和我的团队一直致力于建立一个 哺乳动物精子发生的表观遗传机制的详细图片。我们已经证明 生殖细胞发育中有丝分裂到减数分裂的转变是值得注意的，不仅因为基因的整体变化， 表达，但表观基因组的动态重组;简而言之，我们已经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种系机制， 为今后的研究奠定了坚实的基础。 为了了解关键的性二态过程，我们专注于基本过程， 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，在男性中， 减数分裂性染色体失活（MSCI）的功能作为一个关键的性二态性过程，我们也将 确定DNA损伤反应途径的分子功能-这指导了MSCI-在 性染色体的表观遗传调控。相反，雌性生殖细胞在胚胎中经历减数分裂 并在卵母细胞成熟之前进入减数分裂停滞的延长阶段--在人类中跨越数十年。我们 将确定卵子发生关键阶段的表观遗传机制，以补充我们的研究 男性生殖细胞的细胞。最终，我们将揭示精子发生的独特特征和统一原则 和卵子发生把所有这些放在一起，我们处于独特的地位，以澄清如何基本的种系 机制交叉，以确保基因组的维护，基因组防御和表观遗传基因调控上的一个 系统层面。本申请中提出的研究方向具有凝聚力和协同性， 保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的潜力， 人类生殖和一般生殖健康。

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.