Unscrambling Eggs: TAF4B and Transcriptional Regulation of Meiosis I in Mouse Oocytes

解读鸡蛋：TAF4B 和小鼠卵母细胞减数分裂 I 的转录调控

• 批准号: 10049987
• 负责人: Megan A Gura
• 金额: $ 4.6万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-01 至 2022-01-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10049987
• 关键词: Address; Affect; Aneuploidy; Apoptotic; Back; Binding; Binding Sites; Biochemistry; Cellular biology; Characteristics; Competence; Complex; Cyst; Data; Defect; Development; Embryo; Ensure; Estrus; Event; Failure; Fellowship; Female; Fertility; Gene Expression; Genes; Genetic Transcription; Germ Cells; Goals; Homeobox; Human; Individual; Infertility; International; Knowledge; Laboratory Research; Meiosis; Meiotic Prophase I; Mentors; Messenger RNA; Modeling; Molecular; Molecular Biology; Mus; Newborn Infant; Oocytes; Oogenesis; Ovarian Follicle; Ovary; Patients; Phenotype; Play; Population; Preparation; Primordial Follicle; Process; Proteins; Regulation; Reproduction; Reproductive Biology; Research; Research Training; Role; Serum; Syndrome; TAF4B gene; TATA-Binding Protein Associated Factors; Testing; Time; Training; Transcript; Transcriptional Activation; Transcriptional Regulation; Tretinoin; United States; Universities; Woman; Wood material; Work; career; collaborative environment; egg; experience; female fertility; fetal; frontier; human female; improved; interest; member; mouse genome; ovarian reserve; postnatal; primary ovarian insufficiency; programs; promoter; protein expression; protein protein interaction; reproductive; sex; skills; success; supportive environment; symposium; transcription factor

Project Summary Infertility is a common issue across the United States, with 1% of all women being affected by primary ovarian insufficiency (POI) and 70% of these POI cases being idiopathic. Fertility problems such as POI can be caused by early defects in the development of the ovarian reserve. Meiosis is one such contributor to the success or failure of establishing a healthy primordial follicle pool in the ovarian reserve. Despite the critical importance of meiosis in fertility, the sex-specific characteristics of early female meiosis and the transcriptional controls regulating these early events in the female germline are poorly understood. The focus of my research, and a regulator of meiosis, is TBP-Associated Factor 4B (TAF4B), a gonadally-enriched member of the general transcription machinery. Mice deficient in functional TAF4B have been shown to display multiple aspects of POI and critical defects in early meiotic events and gene expression. The effects of Taf4b-deficiency in the mouse have been traced as far back in development as embryonic day 13.5 (E13.5), when meiosis initiates. I will create a comprehensive model of the transcriptional regulation required for the expression of meiotic genes and successful execution of meiotic initiation via TAF4B. Aim 1 will elucidate the protein characteristics and interactions of TAF4B before, during, and after meiotic initiation. Aim 2 will explore the TAF4B-dependent gene program node of meiotic initiation in female germ cells at E13.5, determining which genes are indirectly or directly regulated by TAF4B and the overall impact on meiotic initiation. This proposal will be of significant interest to the reproductive biology field because it will be the first study to examine how selective components of the general transcription machinery work together with germ-cell specific machinery to promote meiotic initiation. One of this fellowship's training goals is to develop the repertoire of skills and body of knowledge for a successful career in reproductive biology research. The second goal is to gain experience in effectively communicating research in a variety of settings. To achieve these goals, completion of the proposed research, attending the Frontiers in Reproduction course in Woods Hole, presenting at national and international conferences, and the sponsor's mentoring will ensure the success of this training plan. Furthermore, this proposal will take place in the excellent environment of the interdisciplinary and supportive Molecular Biology, Cell Biology, and Biochemistry program at Brown University. Completion of this research and training plan will move the reproductive biology field forward and give the ideal preparation towards the career goal of leading an independent academic research laboratory focused on reproductive biology.

项目摘要 不孕症是美国的一个常见问题，1%的女性受到原发性不孕症的影响。 卵巢功能不全（POI）和70%的这些POI病例是特发性的。生育问题，如POI， 由卵巢储备发育的早期缺陷引起。减数分裂是一个这样的贡献者的成功 或未能在卵巢储备中建立健康的原始卵泡池。尽管至关重要 减数分裂在育性中的作用，早期雌性减数分裂的性别特异性特征和转录调控 在雌性生殖系中调节这些早期事件的机制还知之甚少。我的研究重点， 减数分裂的调节因子是TBP相关因子4B（TAF4B），它是一种富含性腺的一般性调节因子。 转录机器功能性TAF 4B缺陷的小鼠已被证明表现出POI的多个方面 以及早期减数分裂事件和基因表达中的关键缺陷。Taf4b缺乏对小鼠的影响 早在胚胎发育的第13.5天（E13.5），减数分裂开始。我将创建 减数分裂基因表达所需的转录调控的综合模型， 通过TAF4B成功进行减数分裂起始。目的1将阐明蛋白质的特性， TAF4B在减数分裂起始之前、期间和之后的相互作用。目的2探索TAF4B依赖性基因 在E13.5雌性生殖细胞减数分裂起始的程序节点，决定哪些基因是间接或直接 由TAF4B调节和对减数分裂起始的总体影响。这一建议将是重大利益， 生殖生物学领域，因为它将是第一个研究如何选择一般成分， 转录机制与生殖细胞特异性机制一起促进减数分裂起始。其中一 奖学金的培训目标是发展技能和知识体系的剧目，为成功的职业生涯， 生殖生物学研究第二个目标是获得有效传播研究的经验， 各种设置。为了实现这些目标，完成拟议的研究，参加前沿， 在伍兹霍尔举办的生殖课程，在国家和国际会议上发表演讲， 辅导将确保这一培训计划取得成功。此外，该提案将在优秀的 跨学科和支持性分子生物学，细胞生物学和生物化学计划的环境 在布朗大学。这项研究和培训计划的完成将推动生殖生物学领域向前发展 并为领导一个独立的学术研究实验室的职业目标做好理想的准备 专注于生殖生物学

项目成果

Transcription and chromatin regulation by TAF4b during cellular quiescence of developing prospermatogonia.

• DOI: 10.3389/fcell.2023.1270408
• 发表时间: 2023
• 期刊: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
• 影响因子: 5.5
• 作者: Gura, Megan A.;Bartholomew, Myles A.;Abt, Kimberly M.;Relovska, Sona;Seymour, Kimberly A.;Freiman, Richard N.
• 通讯作者: Freiman, Richard N.

The requirement of ubiquitin C-terminal hydrolase L1 in mouse ovarian development and fertility†.

• DOI: 10.1093/biolre/ioac086
• 发表时间: 2022-08-09
• 期刊: BIOLOGY OF REPRODUCTION
• 影响因子: 3.6
• 作者: Woodman, Morgan F.;Ozcan, Meghan C. H.;Gura, Megan A.;De La Cruz, Payton;Gadson, Alexis K.;Grive, Kathryn J.
• 通讯作者: Grive, Kathryn J.