Epigenetic gene regulation in the germline

种系中的表观遗传基因调控

• 批准号: 10581898
• 负责人: Satoshi Namekawa
• 金额: $ 22.01万
• 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/10581898
• 关键词: 3-Dimensional; Address; Administrative Supplement; Biology; CRISPR screen; 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; Life; Maintenance; Meiosis; Microscope; Mitosis; Molecular; Nuclear; Oogenesis; Outcome Study; Ovarian Tissue; Ovary; Pathway interactions; Phase; Positioning Attribute; Process; Production; Public Health; Reproduction; Reproductive Health; Research; Research Support; Sex Chromosomes; Spermatocytes; Spermatogenesis; Testicular Tissue; Testing; Testis; Work; cohesion; egg; epigenetic regulation; epigenome; epigenomics; high resolution imaging; imaging system; innovation; male; next generation; novel; oocyte maturation; parent project; postnatal; programs; response; sexual dimorphism; sperm cell; stem cells; therapy development

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.

抽象的 生物学上最伟大的谜之一是生活如何使生活永存，并继续永久化 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，并且这种复杂性构成 了解生活的永久性和各种治疗的挑战 种系衍生的遗传和表观遗传疾病。在此R35应用程序中，我们的研究方向 收敛以解决以下问题：表观遗传机制如何控制性别 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造一个 控制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 生殖细胞发育中的有丝分裂 - 菌丝过渡不仅是基因的全球变化值得注意的 表达但表观基因组的动态重组；简而言之，我们透露减数分裂本身就是 全球表观基因组重编程的过程。我的研究计划启用了这些概念， 开发的创新方法来解码对于准备下一代至关重要的种系机制， 为未来的研究提供了严格的基础。 要了解关键的性二态过程，我们专注于 精子发生和卵子发生。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根本生理发生，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 减数分裂性染色体灭活（MSCI）是一个关键的性二态过程，我们也将 确定在 性染色体的表观遗传调节。相反，雌性生殖细胞在胚胎中受到减数分裂 并进入长时间的减数分裂逮捕阶段 - 在人类中扫描数十年 - 卵母细胞成熟。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 男性生殖细胞。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。将所有这一切一起融合在一起，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调节 系统水平。本应用中提出的研究指示具有凝聚力和协同作用，高 维持研究进展并为种系生物学的重大变革性进步提供的潜力， 人类繁殖，总体上复制健康。