Molecular Regulation of Mammalian Meiosis

哺乳动物减数分裂的分子调控

• 批准号: 9120895
• 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/9120895
• 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 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; genetic approach; 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生物学重要性，但其一些重要特征在很大程度上无法解释。我们自己和其他人的最新发现表明，其中许多特征都由相同的蛋白质PRDM9控制。我们的长期目标是确定这些对照的相关性，它们的实现方式以及PRDM9如何适应控制减数分裂进展的蛋白质网络。这将通过小鼠中多个PRDM9等位基因的可用性极大地促进这，每种等位基因都以其自身的监管特异性在我们拥有的最有用的哺乳动物实验模型中表达。 PRDM9是一种在其异常领域及其多种分子活性中执行的生物学功能多样性的特殊蛋白质。这项研究的见解将扩展到减数分裂，直到人口遗传学的主要方面，因为热点的位置决定了遗传模式。鉴定人类疾病基因的基因图研究研究；以及进化生物学，因为PRDM9中的等位基因不兼容会产生混合不育。为了解决相关的实验问题，我们在代表多种实验方法的四个项目中组织了一项协调的努力：遗传学（项目A），蛋白质化学（项目B），计算整合（项目0），细胞生物学（项目D）和分子生物学（项目A，B，C和D）。我们的动物资源核心将为小鼠和新的突变菌株提供。细胞生物学核心将提供精子细胞的制剂，并有助于进行芯片实验。计算核心将执行数据管理和分析。我们的长期目标来自以下总体计划目标：a）全面定义PRDM9在重组，转录和配子发生中的调节功能； b）通过识别和表征其与基因组DNA，其他减数分裂蛋白和专门的减数分裂结构的相互作用，来定义PRDM9在减数分裂中的作用； c）通过使用计算技术来构建其分子函数的集成模型，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的Zn手指（ZnF）中的特殊程度的可变性，以阐明Znf -DNA相互作用的复杂性，这些相互作用在基因组调节中无处不在。该计划项目的结果将显着增加对调节减数分裂机制及其参与其他重要生物学过程的机制的理解。