Epigenetic gene regulation in the germline

种系中的表观遗传基因调控

• 批准号: 10708355
• 负责人: Satoshi Namekawa
• 金额: $ 0.93万
• 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/10708355
• 关键词: Address; Administrative Supplement; Award; 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; Grant; Human; Jasminum; Life; Maintenance; Meiosis; Mitosis; Molecular; Oogenesis; Outcome Study; Parents; Pathway interactions; Positioning Attribute; Process; Production; Public Health; Reproduction; Reproductive Health; Research; Sex Chromosomes; Spermatocytes; Spermatogenesis; Work; career development; doctoral student; egg; epigenetic regulation; epigenome; epigenomics; innovation; male; next generation; novel; oocyte maturation; parent grant; parent project; postnatal; pre-doctoral; programs; response; sexual dimorphism; sperm cell; stem cells; therapy development

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.

父母赠款R35 GM141085的项目摘要 生物学上最伟大的谜之一是生活如何永存，并继续永存， 世世代代。哺乳动物种系的一个关键特征是其性二态性：Sper- 结婚和卵子发生。这些二态发育过程本质上是复杂的，这是 复杂性面临着重要的挑战，以了解生活的永久性和发展 各种种系遗传和表观遗传疾病的治疗方法。在此R35应用程序中 我们的研究方向融合了以下问题：表观遗传机制如何gov- ERN在精子发生和卵子发生中明显的性二态过程，最终导致属 功能性精子和鸡蛋？自从我十年前独立以来，我和我的团队就有 努力构建了控制哺乳动物精子的表观遗传机制的详细图片 创世纪。我们已经表明，生殖细胞发育中的有丝分裂 - 菌病转变是不明显的 只有基因表达的全球变化，而是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 是否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，为未来的研究提供了严格的基础。 为了了解关键的性二态过程，我们专注于Sper-的基本过程 结婚和卵子发生。在精子发生中，产后生殖细胞进入干细胞阶段，经历 减数分裂，并维持精子的长期产生。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， 动态性染色体灭活（MSCI）是一个关键的性二态过程，我们还将 终止在发​​作中的DNA损伤响应途径（直接MSCI）的分子函数 - 性别染色体的网络调节。相比之下，雌性生殖细胞在胚胎中受到减数分裂和 进入卵母细胞成熟的长期减数分裂逮捕阶段（在人类中扫描数十年）。我们 将确定卵子发生关键阶段的表观遗传机制，以完成我们的研究 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理 和卵子发生。将所有这一切融合在一起，我们处于独特的位置，以阐明如何基本 种系机制相交以确保基因组维持，基因组防御和表观遗传基因 在系统层面上进行调节。本应用程序中提出的研究指示具有凝聚力和 协同作用，具有较高的潜力来维持研究进展，并为重大的变革性ad- 种系生物学，人类繁殖和复制健康中的范围。