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.

我们已经发现了最近发现的一类基因的意想不到的特性，长非编码（lnc）RNA托管microRNA。在这个提议中，我们的目标是研究这些特性，以了解这些基因是如何被调控的。这些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。人类基因组由非常长的DNA序列组成，在转录过程中复制DNA片段以产生相关分子RNA的链。直到最近，人们还认为大多数RNA分子被用作制造蛋白质的模板，然后蛋白质执行细胞的功能。然而，现在很清楚，我们产生了大量不编码蛋白质的RNA分子。这些被称为非编码RNA，它们的产生和功能大多知之甚少，其中一类非编码RNA我们知道得更多的是microRNA。人类细胞产生超过2000种这样的小RNA，每种小RNA通过与编码它们的RNA分子相互作用来调节一组特定靶蛋白的表达。这种调节在人类健康和疾病中非常重要，许多microRNA与癌症等疾病相关。每个microRNA在特定的时间在特定的细胞类型中表达，正确维持这些表达模式对于正常的健康和发育至关重要。MicroRNA是通过多步途径产生的。控制其生产的最重要步骤是第一步，在转录仍在进行的同时，一个长RNA分子被称为微处理器的分子机器识别和切割。几乎我们所知道的关于microRNA产生的所有信息都来自于一个microRNA基因的子集，这些基因也产生蛋白质编码RNA。然而，至少有一半的人类microRNA位于不同类型的基因中，称为长非编码（lnc）RNA。lncRNA引起了人们极大的兴趣，因为它们在健康和疾病中的多种功能开始被揭示。令人兴奋的最新数据表明，它们的转录和RNA加工不同于蛋白质编码基因。这对microRNA生产的影响目前尚不清楚，将在本提案中确定。这项提议建立在我们以前的工作基础上，我们在工作中确定了lncRNA和蛋白质编码microRNA基因加工的重要差异。我们确定了一种终止转录过程的新机制，这是lncRNA宿主microRNA所独有的。(i)我们将发现这种新机制是如何控制的，并首次展示这两类基因是如何区分的。我们还确定了一个意想不到的作用，RNA加工事件称为剪接在驱动转录的lncRNA托管microRNA，支持剪接是重要的控制microRNA的生产，它差异影响两类microRNA基因的想法。(ii)我们将建立剪接如何控制从lncRNA和蛋白质编码microRNA基因产生microRNA。(iii)我们还将确定控制转录过程本身的因素，以及这两种基因类型之间的差异，如何影响两者的microRNA产生。我们将使用宿主microRNA-122的lncRNA作为解决这些问题的模型，microRNA-122在胆固醇代谢、丙型肝炎病毒感染和肝癌中具有重要的生物学意义。这种方法将与最先进的技术相结合，将我们的分析扩展到所有可检测的microRNA。总之，这项研究的结果将使我们对microRNA生产的控制有前所未有的了解。了解这些控制途径使我们有可能操纵它们，这对未来的医疗和生物技术非常重要。