Roles of small RNAs in guarding germ cell genomes

小RNA在保护生殖细胞基因组中的作用

• 批准号: 8581275
• 负责人: Gregory J Hannon
• 金额: $ 40.64万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581275
• 关键词: Address; Affect; Animals; Area; Beryllium; Binding; Biochemical; Biochemistry; Biogenesis; Biological; Biological Process; Cell Nucleus; Cell physiology; Cells; Chromatin; Chromosome Segregation; Cleaved cell; Code; Complex; Consensus; Cytoplasm; DNA Insertion Elements; Defense Mechanisms; Deposition; Drosophila genus; Elements; Epigenetic Process; Event; Failure; Family; Funding; Gene Expression; Genes; Genetic Transcription; Genome; Genomics; Germ Cells; Germ Lines; Goals; Immune system; Inherited; Lead; Mechanics; Messenger RNA; Mobile Genetic Elements; Modeling; Molecular; Mus; Nuclear; Organism; Parasites; Parents; Pathway interactions; Plant Roots; Play; Population; Process; Production; Progress Reports; Protein Family; Proteins; Regulation; Replication Error; Repression; Role; Signal Transduction; Site; Small RNA; Staging; Tissues; Transcript; Work; base; cofactor; fly; genetic element; insight; neuronal cell body; novel; offspring; piRNA; public health relevance; reproductive; response; transmission process

DESCRIPTION (provided by applicant): It is essential that the genome be passed faithfully from parents to their offspring. Threats to faithful genome transmission come from limitations on the fidelity of replication, errors in chromosome segregation, and from the deleterious activity of parasitic genetic elements, transposons, which propagate by increasing their copy numbers in germ cell genomes. The challenge of transposon control is formidable. In Drosophila, more than 200 different elements are distributed among highly divergent families. These elements use different mobilization strategies and share no universal proteins or cofactors. Thus, the host must somehow discriminate this diversity of elements from protein coding genes and selectively silence the former. Over the past 6 years, we have come to understand that the piRNA pathway plays a critical role in reproductive tissues, embodying an essential defense mechanism against mobile genetic elements. Studies, mainly in Drosophila and mice, have established a molecular framework for how the piRNA pathway operates and have implicated a growing list of protein cofactors in its various stages. While we have produced a coarse model for piRNA production and for the mechanisms by which the pathway silences transposons, we are only just beginning to understand many of the molecular events that form the mechanistic basis of this innate immune system Our goal in this proposal is to address three key, outstanding issues. First, we wish to understand how the definition of a transposon is established in the form of a piRNA repertoire. This entails deciphering the regulation of piRNA generative loci, the mechanisms which mark RNAs to be processed into piRNAs, and the mechanics of piRNA biogenesis. Second, we will uncover the biochemistry of target repression by Piwi protein/piRNA complexes at both the transcriptional and post-transcriptional levels. Third, will probe the functions of maternally inherited piRNAs and their roles in germ cells and in the soma. By accomplishing these aims, we will contribute to the understanding of one of the most deeply rooted biological imperatives, the need to conserve the integrity of the germ line!

描述（由申请人提供）： 必须忠实地将基因组从父母传给他们的后代。对忠实基因组传播的威胁来自对复制的忠诚度，染色体隔离错误以及寄生遗传元件的有害活动，转座子的限制，这些活动是通过在生殖细胞基因组中增加其拷贝数来传播的。转座子控制的挑战是巨大的。在果蝇中，在高度不同的家庭中分布了200多个不同的元素。这些元素使用不同的动员策略，没有共享通用蛋白质或辅助因子。因此，宿主必须以某种方式将这些元素的多样性与蛋白质编码基因区分开，并有选择地使前者保持沉默。在过去的6年中，我们已经了解到，PiRNA途径在生殖组织中起着至关重要的作用，体现了针对移动遗传元件的基本防御机制。研究主要在果蝇和小鼠中，已经建立了一个分子框架，用于如何在其各个阶段进行piRNA途径的操作，并暗示了越来越多的蛋白质辅因子列表。尽管我们为PIRNA生产产生了一个粗糙的模型，并为途径沉默的转座子的机制而言，但我们才刚刚开始了解许多分子事件，这些分子事件构成了这种先天免疫系统的机械基础，但我们的目标是解决三个关键问题。首先，我们希望了解如何以Pirna曲目的形式建立转座子的定义。这需要解释PIRNA生成基因座的调节，标记为PIRNA中的RNA的机制以及PIRNA生物发生的力学。其次，我们将在转录和转录后水平上揭示PIWI蛋白/PIRNA复合物的靶标抑制生物化学。第三，将探测母体遗传的PIRNA及其在生殖细胞和SOMA中的作用。通过实现这些目标，我们将为理解最深层生物学的必要性之一做出贡献，需要保留细菌的完整性！