Define piRNA biogenesis and function in mice

定义小鼠中 piRNA 的生物发生和功能

基本信息

批准号：
10454913
负责人：
Xin Li
金额：
$ 38.5万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

项目摘要

Reproduction is a fundamental feature of life. Animals usually require the differentiation of germ cells to create gametes. The gametogenesis process is delicately regulated, defects in which lead to fertility problems that impact 15% of humans. PIWI-interacting RNAs (piRNAs) are the most recently discovered and rapidly evolving class of small RNAs in animals. In vertebrates, piRNAs are almost exclusively expressed in testis, and they are essential for spermatogenesis. Some piRNAs guide PIWI proteins to silence transposable elements through sequence complementarity; humans, mice, and rooster, however, also produce a distinct and abundant set of non-repetitive piRNA sequences whose targets are unknown. My long-term goal is to understand the biology of piRNAs and their functions in male fertility. There is no obvious conservation of piRNA species, and piRNAs are heterogeneous: an organism carries millions of different piRNA sequences. The diversity is a result of their unusual biogenesis. Long single-stranded piRNA precursors are cleaved into thousands of snippets, and these fragments are loaded into PIWI proteins and become piRNAs. This fragmentation, which is poorly understood, distinguishes piRNA processing from other RNA fates. My previous work defined the precise transcription units of piRNA producing loci in mice, paving the way for the analysis of their post-transcriptional processing and their functions. I have further developed new methodologies and animal models to overcome longstanding roadblocks in piRNA research. In unpublished work, we found that ribosomes appear to participate in piRNA biogenesis, and that piRNAs act to regulate sperm epigenomes including RNAs and histones. Here, I propose to focus on two questions: 1) What principles designate a sequence to become a piRNA? 2) What is the function of piRNAs beyond transposable element silencing in male reproduction? The findings from this work may lead to the discovery of new mechanisms in male fertility and RNA biology.

繁殖是生活的基本特征。动物通常需要分化生殖器才能产生配子。配子发生过程受到细微的调节，缺陷导致生育问题影响15％的人类。 PIWI相互作用RNA（PIRNA）是最近发现的，并且迅速发展动物中的小rnas类。在脊椎动物中，piRNA几乎仅在睾丸中表达，它们是对于精子发生必不可少的。一些PIRNA引导PIWI蛋白通过序列互补性；然而，人类，老鼠和公鸡也产生了一组独特而丰富的集合靶标未知的非竞争性piRNA序列。我的长期目标是了解 PIRNA及其在男性生育中的功能。没有明显的PIRNA物种和PIRNA的保护是异质的：一个生物具有数百万个不同的piRNA序列。多样性是他们的结果异常生物发生。将长的单链PIRNA前体裂解成数千个片段，这些片段片段被加载到PIWI蛋白中并变成PIRNA。这种分散化，知之甚少，将PIRNA加工与其他RNA命运区分开。我以前的工作定义了精确的转录单元在小鼠中产生基因座的piRNA，为分析其转录后处理铺平了道路他们的功能。我进一步开发了新的方法论和动物模型来克服长期 Pirna研究中的障碍。在未发表的工作中，我们发现核糖体似乎参与了皮尔纳生物发生，PIRNA作用是调节包括RNA和组蛋白在内的精子表观基因组。在这里，我建议关注两个问题：1）哪些原则指定序列成为Pirna？ 2）什么是 PIRNA超出男性繁殖中可转座元件沉默的功能？这项工作的发现可能导致发现男性生育能力和RNA生物学的新机制。