Molecular Regulation of Mammalian Meiosis

哺乳动物减数分裂的分子调控

• 批准号: 8723849
• 负责人: KENNETH PAIGEN
• 金额: $ 163.06万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723849
• 关键词: Address; Alleles; Biological; Biological Process; Biology; Cell division; Cellular biology; Chromosome Mapping; Complex; Computational Technique; DNA; Data Analyses; Defect; Embryo; Experimental Models; Fingers; Gametogenesis; Genes; Genetic; Genetic Recombination; Genetic Transcription; Genomic DNA; Genomics; Goals; Human; Hybrids; Infertility; Inheritance Patterns; Instruction; Location; Meiosis; Modeling; Molecular; Molecular Biology; Mus; Nature; Play; Population Genetics; Preparation; Process; Protein Chemistry; Proteins; Regulation; Reproductive Health; Role; Specificity; Spermatocytes; Sterility; Structure; Transcriptional Activation; animal resource; data management; egg; human disease; insight; mutant; programs; research study; sperm cell

DESCRIPTION (provided by applicant): Despite the biological importance of mammalian meiosis, several of its significant features rema n largely unexplained. Recent discoveries by ourselves and others have shown that many of these features are controlled by the same protein, PRDM9. Our long-term objective is to determine how these controls are related, how they are achieved, and how PRDM9 fits into the larger network of proteins controlling meiosis progression. This will be greatly facilitated by the availability of multiple PRDM9 alleles in mice, each with its own regulatory specificities expressed in the most useful mammalian experimental model that we have. PRDM9 is an exceptional protein in the diversity of biological functions it carries out, in its unusual domain structure, and in its diverse molecular activities. The insights this study will provide extend beyond meiosis to major aspects of population genetics, as the location of hotspots determines patterns of inheritance; to genetic mapping studies identifying human disease genes; and to evolutionary biology, as allelic incompatibilities in PRDM9 can produce hybrid sterility. To address the relevant experimental questions, we have organized a coordinated effort among four projects representing diverse experimental approaches: genetics (Project A), protein chemistry (Project B), computational integration (Project 0), cell biology (Project D), and molecular biology (Projects A, B, C and D). Our Animal Resources Core will provide mice and new mutant strains. A Cell Biology Core will provide preparations of spermatocytes and assist in ChIP experiments. The Computational Core will perform data management and analysis. Our long-term objectives derive from the following overall program goals: a) Comprehensively define PRDM9's regulatory functions in recombination, transcription, and gametogenesis; b) Define the role of PRDM9 in regulation of meiosis by identifying and characterizing its interactions with genomic DNA, other meiotic proteins, and specialized meiotic structures; c) Define the overall role of PRDM9 in gametogenesis, hotspot activation, and transcription by using computational techniques to build an integrated model of its molecular functions; and d) Exploit the exceptional degree of variability in the Zn fingers (ZNF) of PRDM9 to clarify the complex nature of ZNF - DNA interactions, which are so ubiquitous in genomic regulation. Results of the program project will significantly increase the understanding of the mechanisms that regulate meiosis as well as their involvement in other important biological processes.

描述（由申请人提供）： 尽管哺乳动物减数分裂具有重要的生物学意义，但它的一些重要特征在很大程度上仍然无法解释。我们和其他人最近的发现表明，其中许多特征是由同一种蛋白质 PRDM9 控制的。我们的长期目标是确定这些控制如何相关、如何实现以及 PRDM9 如何融入控制减数分裂进程的更大蛋白质网络。小鼠体内多个 PRDM9 等位基因的可用性将极大地促进这一点，每个等位基因在我们拥有的最有用的哺乳动物实验模型中都有其自己的调控特异性。 PRDM9 是一种特殊的蛋白质，它具有多种生物功能、不寻常的结构域结构以及多种分子活性。这项研究将提供的见解将超越减数分裂扩展到群体遗传学的主要方面，因为热点的位置决定遗传模式；识别人类疾病基因的基因图谱研究；对于进化生物学来说，PRDM9 中的等位基因不相容性会产生杂种不育。为了解决相关的实验问题，我们组织了代表不同实验方法的四个项目之间的协调工作：遗传学（项目 A）、蛋白质化学（项目 B）、计算集成（项目 0）、细胞生物学（项目 D）和分子生物学生物学（项目 A、B、C 和 D）。我们的动物资源核心将提供小鼠和新的突变品系。细胞生物学核心将提供精母细胞制剂并协助 ChIP 实验。计算核心将执行数据管理和分析。我们的长期目标源自以下总体计划目标： a) 全面定义 PRDM9 在重组、转录和配子发生方面的调控功能； b) 通过鉴定和表征 PRDM9 与基因组 DNA、其他减数分裂蛋白和特殊减数分裂结构的相互作用，定义 PRDM9 在减数分裂调节中的作用； c) 通过使用计算技术建立其分子功能的集成模型，定义PRDM9在配子发生、热点激活和转录中的总体作用； d) 利用 PRDM9 锌指 (ZNF) 的异常程度的变异性来阐明 ZNF - DNA 相互作用的复杂性质，这种相互作用在基因组调控中普遍存在。该计划项目的结果将显着增进对调节减数分裂机制及其参与其他重要生物过程的理解。