ChemDecEpi: A Chemical Synthesis Approach towards Decoding the Epitranscriptome

ChemDecEpi：解码表观转录组的化学合成方法

• 批准号: EP/X032043/1
• 负责人: Matthew Gaunt
• 金额: $ 273.74万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX032043%2F1
• 关键词: ChemDecEpi; Chemical; Synthesis; Approach; towards

Beyond the core information stored in the sequence of RNA, a second layer of programming exists in the form of a large number of chemical modifications to the canonical nucleobases. Over 140 distinct variations have been identified in RNA. These post-transcriptionally modified ribonucleotides play integral roles in the cellular control of information encoded in the gene & are prevalent across all RNA types and are collectively referred to as the epitranscriptome. As well as being pervasive, RNA modifications are also conserved & critical to many aspects of biology and are thought to impact on approximately 16000 human genes. The sheer diversity of RNA modification means that a variety of tools are needed to fully explore the epitranscriptome. Currently, most of the methods for the detection of modified RNAs use an antibody that is selective for a particular modification. While numerous variations exist, they do not always provide single-nucleotide resolution in a general sense and are only a handful of RNA modifications exist, so many modified ribonucleotides are invisible to these detection techniques. There is an unmet need for new reliable & robust methods that target modified RNA structures. This proposal will focus on developing diverse chemistry that selectively targets modifications to RNA, which would offer a synthetic toolkit for tracking across the epitranscriptome. The breadth & flexibility of easily tuneable synthetic transformations means that the intrinsic reactive properties of the chemical features in RNA modifications could be exploited by different activation modes designed to install a functional label or tag, thereby opening the door to detection via established methods such as next generation sequencing. Therefore, from a starting point of new selective chemistry, reaction design using the full spectrum of distinct chemical activation modes this proposal will open many opportunities for new discoveries in the chemistry & biology of RNA.

除了存储在RNA序列中的核心信息之外，第二层编程以大量化学修饰的形式存在于规范的核碱基中。在RNA中已经确定了超过140个不同的变化。这些转录后修饰的核糖核苷酸在基因和基因中编码的信息的细胞控制中起着不可或缺的作用。除了普遍存在，RNA的修饰也对生物学的许多方面也保存和至关重要，并且被认为会影响大约16000个人类基因。 RNA修饰的纯粹多样性意味着需要各种工具来充分探索表面翻译。当前，检测改良RNA的大多数方法都使用针对特定修饰的选择性的抗体。尽管存在许多变化，但它们并不总是从一般意义上提供单核苷酸分辨率，并且仅存在一些RNA修饰，因此这些检测技术是看不见的许多修饰的核糖核苷酸。靶向修改的RNA结构的新的可靠和鲁棒方法的需求未满足。该提案将着重于开发各种化学反应，该化学反应有选择地针对RNA的修改，该化学方法将提供一个合成工具包，用于跟踪整个上皮分类组。易于调谐的合成转换的广度和灵活性意味着，可以通过旨在安装功能标签或标签的不同激活模式来利用RNA修饰中化学特征的固有反应性能，从而通过既定方法（例如下一代测序）打开检测大门。因此，从新的选择性化学的起点，使用全面的化学激活模式的反应设计该提案将为RNA化学和生物学中的新发现打开许多机会。