Epigenetic gene regulation in the germline

父母补助金项目摘要R35 GM 141085 生物学中最大的谜团之一是关于生命是如何延续的， 代代相传哺乳动物生殖系的一个关键特征是它的两性异形： matogenesis和oogenesis。这些二态发育过程本质上是复杂的， 复杂性对理解生命的永恒性和生命的发展构成了重大挑战。 治疗各种生殖系衍生的遗传和表观遗传疾病。因此，在该R35应用中， 我们的研究方向集中在解决以下问题：表观遗传机制如何调节 在精子发生和卵子发生中存在明显的性二态过程，最终在属- 功能性精子和卵子？自从我十年前独立以来，我和我的团队 致力于构建一幅关于哺乳动物精子的表观遗传机制的详细图片， 创世纪我们已经证明，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， 只有基因表达的全局变化，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就是一个全局表观基因组重编程的过程。我的研究项目 开创了这些概念，并开发了创新的方法来解码生殖细胞机制 这对培养下一代至关重要，为未来的研究提供了坚实的基础。 为了了解关键的性二态过程，我们专注于基本的过程中， matogenesis和oogenesis。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，重点是动态 表观遗传机制的变化及其对下一代的重要性。因为，在男性中，梅- 耳性染色体失活（MSCI）的功能作为一个关键的性二态性过程，我们也将去- 确定DNA损伤反应途径的分子功能- 性染色体的遗传调节。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，以补充我们对 男性生殖细胞最终，我们将揭示精子发生的独特特征和统一原则 和卵子发生综上所述，我们处于独特的地位，可以阐明 种系机制交叉以确保基因组维持、基因组防御和表观遗传基因 在系统层面上进行监管。本申请中提出的研究方向具有凝聚力， 协同增效，具有维持研究进展的高潜力，并为重大的变革性广告提供信息， 在生殖生物学、人类生殖和一般生殖健康方面的进展。

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.