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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 In unpublished work, we found that ribosomes appear to participate in piRNA biogenesis, and that piRNAs act to regulate sperm epigenomes including RNAs and histones.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.

生殖是生命的基本特征。动物通常需要生殖细胞的分化来创造配子配子发生过程受到微妙的调节，其中的缺陷导致生育问题，影响了15%的人类。PIWI相互作用RNA（piRNA）是最近发现并迅速进化的动物体内的一类小RNA。在脊椎动物中，piRNA几乎仅在睾丸中表达，并且它们在睾丸中表达。对精子生成至关重要。一些piRNA引导PIWI蛋白通过以下途径沉默转座因子：序列互补性;然而，人类、小鼠和公鸡也产生一组独特且丰富的靶点未知的非重复皮尔纳序列。我的长期目标是了解 piRNA及其在男性生育中的功能。皮尔纳种类没有明显的保守性，并且piRNA 是异质的：一个生物体携带数百万个不同的皮尔纳序列。这种多样性是他们不寻常的生物起源长的单链皮尔纳前体被切割成数千个片段，这些片段被称为piRNA。片段被加载到PIWI蛋白中并成为piRNA。这种碎片化，人们对此知之甚少，将皮尔纳加工与其他RNA命运区分开来。我之前的工作定义了精确的转录单位小鼠中皮尔纳产生位点的研究，为分析其转录后加工和它们的功能。我进一步开发了新的方法和动物模型，以克服长期存在的皮尔纳研究中的障碍。在未发表的工作中，我们发现核糖体似乎参与皮尔纳，生物发生，并且piRNA用于调节精子表观基因组，包括RNA和组蛋白。在这里，我建议重点关注两个问题：1）是什么原则指定一个序列成为皮尔纳？2)是什么 piRNA在男性生殖中除了转座因子沉默之外的功能？这项工作的发现可能导致发现男性生育力和RNA生物学的新机制。