Regulation of microRNA biogenesis from long noncoding RNAs

长非编码 RNA 的 microRNA 生物合成的调控

• 批准号: BB/S003908/1
• 负责人: Catherine Jopling
• 金额: $ 58.55万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS003908%2F1
• 关键词: Regulation; microRNA; biogenesis; long; noncoding

We have discovered unexpected properties of a recently identified class of genes, long noncoding (lnc)RNAs hosting microRNAs. In this proposal, we aim to investigate these properties in order to understand how these genes are regulated. This new knowledge will be essential for understanding normal development and diseases such as cancer, and may lead to the development of new therapeutic strategies.The human genome is composed of very long sequences of DNA, sections of which are copied in the process of transcription to produce strands of a related molecule known as RNA. Until recently it was thought that most RNA molecules are used as templates to make proteins, which then carry out a cell's functions. However, it is now clear that we produce vast numbers of RNA molecules that do not encode proteins. These are known as noncoding RNAs and their production and function are mostly very poorly understood.One class of noncoding RNAs that we know more about is microRNAs. Human cells produce over 2000 of these small RNAs, each of which functions to regulate expression of a particular set of target proteins by interacting with the RNA molecules that encode them. This regulation is very important in human health and disease, with many microRNAs associated with diseases such as cancer. Each microRNA is expressed in specific cell types at specific times, and it is essential for normal health and development that these expression patterns are maintained correctly. MicroRNAs are produced by a multi-step pathway. The most important step in controlling their production is the first one, in which a long RNA molecule is recognised and cut by a molecular machine called the Microprocessor while transcription is still in progress. Almost all we know about microRNA production comes from a subset of microRNA genes that also produce protein coding RNAs. However, at least half of human microRNAs are instead located in a different type of gene, known as long noncoding (lnc)RNAs. LncRNAs are of great interest as their diverse functions in health and disease are beginning to be revealed. Exciting recent data shows that their transcription and RNA processing are different to those of protein coding genes. The consequences of this for microRNA production are currently unknown, and will be determined in this proposal. This proposal builds on our previous work in which we identified important differences in the processing of lncRNA and protein coding microRNA genes. We identified a new mechanism of terminating the transcription process that is unique to lncRNAs hosting microRNAs. (i) We will find out how this new mechanism is controlled, showing for the first time how these two classes of gene are distinguished. We have also identified an unexpected role for an RNA processing event known as splicing in driving transcription of lncRNAs hosting microRNAs, supporting the idea that splicing is important in controlling microRNA production and that it differentially affects the two classes of microRNA genes. (ii) We will establish how splicing controls microRNA production from both lncRNA and protein coding microRNA genes. (iii) We will also determine how factors that control the process of transcription itself, and differ between these two gene classes, influence microRNA production from both. We will use the lncRNA that hosts microRNA-122, which is biologically important in cholesterol metabolism, hepatitis C virus infection, and liver cancer, as a model to address these questions. This approach will be coupled with state-of-the art techniques to extend our analysis to all detectable microRNAs.Together, the results of this research will give unprecedented understanding of the control of microRNA production. Understanding these control pathways gives us the potential to manipulate them, which could be very important in the future for medical treatments and biotechnology.

我们发现了最近鉴定出的基因类别的意外特性，长期不编码（LNC）托管microRNA。在此提案中，我们旨在研究这些特性，以了解如何调节这些基因。这种新知识对于理解正常发育和癌症等疾病至关重要，并可能导致新的治疗策略的发展。人类基因组由很长的DNA序列组成，其部分在转录过程中复制以产生相关分子的链，称为RNA。直到最近，人们认为大多数RNA分子被用作制造蛋白质的模板，然后执行细胞的功能。但是，现在很明显，我们产生了不编码蛋白质的大量RNA分子。这些被称为非编码RNA，它们的生产和功能大多是非常了解的。我们对MicroRNA的了解更多的非编码RNA类别。人类细胞在2000年以上产生这些小RNA，每种RNA都通过与编码它们的RNA分子相互作用来调节特定靶蛋白的表达。该调节在人类健康和疾病中非常重要，许多与癌症等疾病有关的微洋疾病。每种microRNA在特定时间以特定的细胞类型表达，对于正常健康和发育至关重要，这些表达模式可以正确地保持。 microRNA由多步途径产生。控制其生产的最重要步骤是第一个，其中长RNA分子被称为微处理器的分子机识别并切割，而转录仍在进行中。我们几乎所有关于microRNA生产的知识都来自也产生蛋白质编码RNA的microRNA基因的子集。但是，至少有一半的人类microRNA位于不同类型的基因中，称为长期编码（LNC）RNA。 LNCRNA引起了人们的极大兴趣，因为它们在健康和疾病中的多种功能开始揭示。令人兴奋的最近数据表明，它们的转录和RNA处理与蛋白质编码基因的转录和RNA处理不同。目前，这对microRNA生产的后果尚不清楚，并将在此提案中确定。该提议建立在我们以前的工作的基础上，在这些工作中，我们确定了LNCRNA和蛋白质编码microRNA基因的加工中的重要差异。我们确定了一种终止转录过程的新机制，该过程是托管microRNA所独有的转录过程。 （i）我们将找出如何控制这种新机制，这是首次如何区分这两个类别的基因。我们还确定了称为剪接的RNA处理事件在驱动托管microRNA的转录中的意外作用，这支持了以下思想：剪接在控制microRNA生产方面很重要，并且它会差异地影响两类的microRNA基因。 （ii）我们将确定剪接如何控制LNCRNA和蛋白质编码microRNA基因的microRNA产生。 （iii）我们还将确定如何控制转录过程本身的因素以及这两个基因类别之间的不同，都会影响两者的microRNA产生。我们将使用托有MicroRNA-122的LNCRNA，该LNCRNA在胆固醇代谢，丙型肝炎病毒感染和肝癌中在生物学上很重要，作为解决这些问题的模型。这种方法将与最先进的技术相结合，以将我们的分析扩展到所有可检测的microRNA。了解这些控制途径使我们有可能操纵它们，这对于将来的医疗治疗和生物技术可能非常重要。