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The role of small RNA derived tRNAs in gene regulation: Mechanism and Therapeutic Applications

小RNA衍生的tRNA在基因调控中的作用：机制和治疗应用

基本信息

批准号：
9763548
负责人：
Mark A Kay
金额：
$ 51.03万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763548
关键词：
Affect Antisense Oligonucleotides Apoptosis Biogenesis Cell Death Cell Proliferation Cell Survival Cells Code Complement Data Defect Dose Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genome Goals High-Throughput Nucleotide Sequencing Human Implant Leucine Literature Liver Liver neoplasms Malignant Neoplasms Mammalian Cell Mammals Measures Mediating Medical Messenger RNA Modeling Modernization Molecular Mus Oligonucleotides Organism Patients Phenotype Play Population Porifera Primary carcinoma of the liver cells Process Proteins RNA RNA, Ribosomal, 18S Regulation Regulator Genes Regulatory Pathway Ribosomal Proteins Ribosomes Role Safety Signal Transduction Small RNA Structure Testing Therapeutic Tissues Transfer RNA Translations Untranslated RNA Variant Xenograft procedure adeno-associated viral vector base cell growth dark matter differential expression falls gene therapy human disease in vivo individual patient knock-down mammalian genome mouse model new therapeutic target novel preclinical efficacy response therapeutic target transgene expression tumor tumor growth

项目摘要

ABSTRACT One of the most important concepts in modern genetics is the realization that over 90% of the mammalian genome is transcribed into RNA. These non-protein coding RNAs have been described as the dark matter of the genome as the function of most of these RNAs has yet to be determined. Just over 5 years ago, we stumbled onto a novel set of tRNA derived small RNAs (tsRNAs). These tRNA derived fragments are also commonly called trfRNAs, and were originally thought to represent degradation products. However, it is now clear there are hundreds or perhaps thousands of different RNA fragments generated in mammalian cells and there is increasing evidence that these are functionally important. As a group, they have been proposed to regulate genes at many different levels. We plan to study the 3’tsRNAs (derived from the 3’ end of the mature tRNA) currently the least well studied of the various types of fragments, and for which no definitive function has yet to be described. We have established that one specific RNA, the 22nt CAG-Leucine 3’tsRNA when down regulated by the addition of antisense oligonucleotides in rapidly dividing cells inhibits ribosome biogenesis by first limiting the translation of at least one ribosomal protein mRNA. This results in rapid cellular apoptosis. In contrast, the addition of a 3’tsRNA mimic increases cellular proliferation and can complement the ribosome biogenesis defects in cells. These data bring to light a previously unknown post- transcriptional gene regulatory pathway. We plan to further explore the mechanism of how this specific 3’tsRNA-mediates translational gene regulation as well as use new high-throughput sequencing approaches to identify and then test other 3’tsRNAs that may participate in similar types of gene regulation. Finally, we propose to use gene therapy and oligonucleotide antisense delivery to pursue the therapeutic potential of manipulating 3’tsRNAs in treating medical conditions that affect the liver. We believe unraveling the molecular mechanism of this regulatory circuit is important both to further understand how genes are regulated and will provide novel therapeutic targets.

摘要现代遗传学中最重要的概念之一是认识到90%以上的哺乳动物基因组被转录成RNA。这些非蛋白质编码的RNA被描述为暗物质作为这些RNA中的大多数的功能的基因组尚未确定。就在5年前，我们偶然发现了一组新的tRNA衍生的小RNA(TsRNAs)。这些tRNA衍生片段也是通常被称为trfRNAs，最初被认为代表降解产物。然而，现在是显然，在哺乳动物细胞中产生了成百上千种不同的RNA片段越来越多的证据表明，这些在功能上很重要。作为一个群体，他们已经被提议在许多不同的水平上调节基因。我们计划研究3‘tsRNAs(源自3’端的成熟的tRNA)是目前研究最少的各种类型的片段，对于它还没有确定的功能尚未描述。我们已经确定了一种特殊的RNA，即22nt的CAG-亮氨酸 3‘tsRNA在快速分裂细胞中被反义寡核苷酸下调时抑制核糖体生物发生，首先限制至少一种核糖体蛋白mRNA的翻译。这将导致快速的细胞凋亡。相比之下，添加3‘tsRNA模拟物可以促进细胞增殖，并可以补充细胞中的核糖体生物发生缺陷。这些数据揭示了一个以前不为人知的帖子- 转录基因调控途径。我们计划进一步探索这一具体的机制如何 3‘tsRNA-介导翻译基因调控以及使用新的高通量测序方法识别并测试其他可能参与类似类型基因调控的3‘tsRNA。最后，我们建议使用基因治疗和寡核苷酸反义递送来追求肿瘤的治疗潜力在治疗影响肝脏的疾病中操纵3‘tsRNA。我们相信解开这种调节回路的分子机制对于进一步了解基因是如何并将提供新的治疗靶点。