Epigenetic gene regulation in the germline

种系中的表观遗传基因调控

基本信息

批准号：
10181164
负责人：
Satoshi Namekawa
金额：
$ 60.85万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-05 至 2026-06-30
项目状态：
未结题

项目摘要

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.

生物学上最伟大的奥秘之一是生活如何永存，并继续世代相传。哺乳动物种系的关键特征是其性二态性：精子发生和卵子发生。这些二态发育过程本质上是复杂的，这种复杂性给予了重大挑战了解生命的永久性和各种种系衍生的疗法的发展遗传和表观遗传疾病。因此，在此R35应用程序中，我们的研究方向汇聚解决以下问题：表观遗传机制如何在性方面控制独特精子发生和卵子发生中的二态过程，最终产生功能精子和鸡蛋？自从我十年前独立以来，我和我的团队一直在努力建设控制哺乳动物精子发生的表观遗理机制的详细图片。我们已经表明，生殖细胞发育中的有丝分裂 - 菌丝过渡不仅是基因表达的全球变化，但表观基因组的动态重组；简而言之，我们已经揭示了减数分裂本身是全球表观基因组重编程的过程。我的研究计划开创了这些概念，并开发了创新的方法来解码种系机制对于准备下一代至关重要，为未来提供了严格的基础研究。要了解关键的性二态过程，我们专注于基本精子发生和卵子发生的过程。在精子发生中，产后生殖细胞进入茎细胞阶段，经历减数分裂，并维持精子的长期产生。我们将阐明从干细胞阶段到精子的精子发生的全球表观遗传机制生产，重点是表观遗传机械及其的动态变化对下一代的重要性。因为在男性中，减数分裂性染色体灭活（MSCI）作为关键的性二态过程，我们还将确定 DNA损伤反应途径 - 直接MSCL-IN性染色体的表观遗传调节。相比之下，雌性生殖细胞在胚胎中经历减数分裂，并进入一个长时间的阶段在人类成熟的人类中，减数分裂的跨度数十年。我们将确定卵子发生关键阶段的表观遗传机制，以补充我们对雄性生殖细胞。最终，我们将揭示不同的特征和统一原则精子发生和卵子发生。将所有这一切融为一体，我们是独特的定位来澄清基本种系机制如何相交以确保基因组维持，基因组防御和在全身水平上调节表观遗传基因。此处提出的研究指示应用具有凝聚力和协同作用，具有维持研究的高潜力进步并为生物学生物学的重大变革性进步提供信息繁殖和生殖健康。