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 microRNA 的长非编码 (lnc)RNA。在本提案中，我们的目标是研究这些特性，以了解这些基因是如何受到调控的。这些新知识对于理解正常发育和癌症等疾病至关重要，并可能导致新治疗策略的开发。人类基因组由很长的 DNA 序列组成，其中的片段在转录过程中被复制到产生称为 RNA 的相关分子链。直到最近，人们还认为大多数 RNA 分子都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，现在很明显，我们产生大量不编码蛋白质的RNA分子。这些被称为非编码 RNA，人们对它们的产生和功能大多知之甚少。我们更了解的一类非编码 RNA 是 microRNA。人类细胞产生超过 2000 种这样的小 RNA，每种小 RNA 的功能都是通过与编码它们的 RNA 分子相互作用来调节一组特定靶蛋白的表达。这种调节对于人类健康和疾病非常重要，许多 microRNA 与癌症等疾病相关。每个 microRNA 在特定时间在特定细胞类型中表达，正确维持这些表达模式对于正常健康和发育至关重要。 MicroRNA 通过多步骤途径产生。控制它们生产的最重要步骤是第一步，其中长RNA分子被称为微处理器的分子机器识别并切割，同时转录仍在进行中。我们对 microRNA 生产的了解几乎全部来自 microRNA 基因的子集，这些基因也产生编码蛋白质的 RNA。然而，至少一半的人类 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。最近令人兴奋的数据表明，它们的转录和 RNA 加工与蛋白质编码基因不同。目前尚不清楚这对 microRNA 生产的影响，并将在本提案中确定。该提案建立在我们之前的工作基础上，我们在之前的工作中发现了 lncRNA 和蛋白质编码 microRNA 基因加工中的重要差异。我们发现了一种终止转录过程的新机制，这是承载 microRNA 的 lncRNA 所独有的。 （i）我们将找出这种新机制是如何控制的，首次展示这两类基因是如何区分的。我们还发现了一种被称为剪接的 RNA 加工事件在驱动 microRNA 的 lncRNA 转录中发挥着意想不到的作用，这支持了剪接在控制 microRNA 产生中很重要并且它对两类 microRNA 基因有不同影响的观点。 (ii) 我们将确定剪接如何控制 lncRNA 和编码 microRNA 基因的蛋白质的产生 microRNA。 (iii) 我们还将确定控制转录过程本身的因素以及这两个基因类别之间的差异如何影响两者的 microRNA 产生。我们将使用承载 microRNA-122 的 lncRNA 作为模型来解决这些问题，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，这项研究的结果将为 microRNA 生产的控制提供前所未有的理解。了解这些控制途径使我们有可能操纵它们，这对于未来的医疗和生物技术可能非常重要。