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.

我们发现了最近发现的一类基因的意想不到的特性，即承载microRNAs的长非编码(LNC)RNA。在这项提案中，我们的目标是研究这些特性，以了解这些基因是如何调控的。这一新知识将对理解正常发育和癌症等疾病至关重要，并可能导致新治疗策略的开发。人类基因组由非常长的DNA序列组成，其中一部分在转录过程中被复制，以产生被称为RNA的相关分子链。直到最近，人们还认为大多数RNA分子被用作模板来制造蛋白质，然后蛋白质执行细胞的功能。然而，现在很明显，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被理解得很差。我们知道更多的一类非编码RNA是微RNA。人类细胞产生了超过2000个这样的小RNA，每个小RNA都通过与编码它们的RNA分子相互作用来调节一组特定目标蛋白质的表达。这一调控对人类健康和疾病非常重要，许多microRNAs与癌症等疾病有关。每个microRNA在特定的时间在特定的细胞类型中表达，正确地维持这些表达模式对于正常的健康和发育至关重要。MicroRNAs是通过多步途径产生的。控制它们生产的最重要的步骤是第一步，在转录仍在进行中的时候，一台名为微处理器的分子机器识别并切割一个长RNA分子。我们所知道的关于microRNA生产的几乎所有信息都来自于microRNA基因的一个子集，这些基因也能产生编码RNA的蛋白质。然而，至少有一半的人类microRNA位于一种不同类型的基因中，即所谓的长非编码(LNC)RNA。随着其在健康和疾病中的不同功能开始被揭示，lncRNAs引起了极大的兴趣。令人兴奋的最新数据表明，它们的转录和RNA处理不同于蛋白质编码基因。这对microRNA生产的影响目前尚不清楚，将在这项提案中确定。这一建议建立在我们之前的工作的基础上，在那项工作中，我们确定了lncRNA和蛋白质编码的microRNA基因在处理方面的重要差异。我们发现了一种新的终止转录过程的机制，这种机制是承载microRNAs的lncRNAs所特有的。(I)我们将了解这一新机制是如何控制的，首次展示这两类基因是如何区分的。我们还发现了一种名为剪接的RNA加工事件在驱动承载microRNAs的lncRNAs转录方面发挥了意想不到的作用，支持了剪接在控制microRNA生产中的重要性，并对这两类microRNA基因产生了不同的影响。(Ii)我们将确定剪接如何控制lncRNA和编码蛋白质的microRNA基因的microRNA生产。(Iii)我们还将确定控制转录过程本身的因素，以及这两个基因类别之间的差异，如何影响两者产生的microRNA。我们将使用携带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方面具有重要的生物学意义。这一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到的microRNA。同时，这项研究的结果将使人们对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，这在未来的医疗和生物技术中可能非常重要。