Epigenetic gene regulation in the germline

种系中的表观遗传基因调控

• 批准号: 10655598
• 负责人: Satoshi Namekawa
• 金额: $ 68.85万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10655598
• 关键词: Address; Biology; Complement; Complex; DNA Damage; Defect; Development; Developmental Process; Disease; Embryo; Ensure; Epigenetic Process; Female; Foundations; Gene Expression; Gene Expression Regulation; Generations; Genetic; Genome; Germ Cells; Global Change; Human; Life; Maintenance; Meiosis; Mitosis; Molecular; Oogenesis; Outcome Study; Pathway interactions; Positioning Attribute; Process; Production; Public Health; Reproduction; Reproductive Health; Research; Sex Chromosomes; Spermatocytes; Spermatogenesis; Work; egg; epigenetic regulation; epigenome; epigenomics; innovation; male; next generation; novel; oocyte maturation; postnatal; programs; response; sexual dimorphism; sperm cell; stem cells; therapy development

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.

生物学中最大的谜团之一是关于生命是如何延续下去的，并继续下去。 从一代延续到一代。哺乳动物生殖系的一个关键特征是 性二态性：精子发生和卵子发生。这些二态发育的 过程本身就很复杂，这种复杂性对以下方面提出了重大挑战： 了解生命的永恒和各种生殖源性疾病的治疗方法的发展， 遗传和表观遗传疾病。因此，在R35应用中，我们的研究方向趋同 为了解决以下问题：表观遗传机制如何控制不同的性行为， 精子发生和卵子发生的二态过程，最终产生功能性的 精子和卵子自从十年前独立以来，我和我的团队一直致力于建设 一幅关于哺乳动物精子发生的表观遗传机制的详细图片。我们 已经表明，生殖细胞发育中有丝分裂到减数分裂的转变不仅值得注意， 基因表达的整体变化，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 一个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 为下一代做好准备至关重要的机制，为未来的发展奠定坚实的基础。 research. 为了了解关键的性二态过程，我们专注于基本的 精子发生和卵子发生的过程。在精子发生中，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。我们将阐明 精子发生从干细胞阶段到精子的整体表观遗传机制 生产，重点是表观遗传机制及其 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） 功能作为一个关键的性二态性过程，我们还将确定的分子功能， 性染色体表观遗传调控中的DNA损伤反应途径--指导MSCl。 相反，雌性生殖细胞在胚胎中经历减数分裂，并进入一个延长的阶段， 人类在卵母细胞成熟之前，减数分裂停滞长达数十年。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 精子发生和卵子发生。综上所述，我们处于独特的地位， 基本的种系机制如何相互交叉，以确保基因组的维护，基因组防御， 系统水平上的表观遗传基因调控。本文提出的研究方向 应用程序是有凝聚力和协同作用的，具有很大的潜力，以维持研究 在生殖系生物学、人类基因组学和人类基因组学领域取得进展， 生殖和一般生殖健康。