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.

家长补助金 R35 GM141085 项目摘要 生物学中最大的谜团之一是生命如何延续并继续延续， 哺乳动物种系的一个关键特征是其性别二态性：精子。 这些二态性发育过程本质上是复杂的，并且这一点。 复杂性对理解生命的永恒性和生命的发展提出了重大挑战 因此，在该 R35 应用中，治疗各种种系衍生的遗传和表观遗传疾病。 我们的研究方向集中于解决以下问题：表观遗传机制如何控制 精子发生和卵子发生过程中存在性别不同的二态性过程，最终导致生殖 自从十年前我独立以来，我和我的团队已经 致力于构建控制哺乳动物精子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到减数分裂的转变是值得注意的。 简而言之，只有基因表达的全局变化，以及表观基因组的动态重组； 我的研究项目揭示了减数分裂本身是一个全球表观基因组重编程的过程。 开创了这些概念并开发了解码种系机制的创新方法 对于准备下一代至关重要，为未来的研究提供坚实的基础。 为了理解关键的性二态性过程，我们关注超级性别二态性的基本过程。 精子发生和卵子发生过程中，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潜在精子发生，重点是动态 表观遗传机制的变化及其对下一代的重要性。 耳性染色体失活（MSCI）是一个关键的性二态性过程，我们还将去- 终止DNA损伤反应途径的分子功能——指导MSCI——在表观- 相反，雌性生殖细胞在胚胎和胚胎中经历减数分裂。 在卵母细胞成熟之前，进入减数分裂的长期停滞阶段（在人类中长达数十年）。 将确定卵子发生关键阶段的表观遗传机制，以补充我们的研究 最终，我们将揭示精子发生的独特特征和统一原理。 将所有这些结合在一起，我们具有独特的优势来阐明其基础性。 种系机制交叉以确保基因组维护、基因组防御和表观遗传基因 本申请提出的研究方向具有凝聚力和一致性。 协同作用，具有维持研究进展并为重大、变革性广告提供信息的巨大潜力 种系生物学、人类生殖和一般生殖健康的进步。