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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：
10875713
负责人：
Satoshi Namekawa
金额：
$ 2.97万
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.

生物学中最大的谜团之一是生命是如何延续并继续存在的

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

PRC1 suppresses a female gene regulatory network to ensure testicular differentiation.

DOI：
10.1038/s41419-023-05996-6
发表时间：
2023-08-04
期刊：
CELL DEATH & DISEASE
影响因子：
9
作者：
Maezawa, So;Yukawa, Masashi;Hasegawa, Kazuteru;Sugiyama, Ryo;Iizuka, Mizuho;Hu, Mengwen;Sakashita, Akihiko;Vidal, Miguel;Koseki, Haruhiko;Barski, Artem;DeFalco, Tony;Namekawa, Satoshi H. H.
通讯作者：
Namekawa, Satoshi H. H.

Bioinformatics Pipelines for Identification of Super-Enhancers and 3D Chromatin Contacts.

用于识别超级增强子和 3D 染色质接触的生物信息学流程。