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序列中的核心信息外，第二层编程以对标准核苷酸碱基进行大量化学修饰的形式存在。已经在RNA中发现了140多种不同的变异。这些转录后修饰的核苷酸在编码在基因中的信息的细胞控制中发挥着不可或缺的作用，普遍存在于所有类型的RNA中，统称为表位转录组。除了普遍存在外，核糖核酸的修饰也是保守的，对生物学的许多方面都至关重要，被认为影响了大约16000个人类基因。RNA修饰的绝对多样性意味着需要各种工具来充分探索表观转录组学。目前，大多数检测修饰RNA的方法都使用对特定修饰具有选择性的抗体。虽然存在许多变体，但它们并不总是提供一般意义上的单核苷酸分辨率，并且只存在少数几种RNA修饰，因此许多修饰的核苷酸对于这些检测技术是不可见的。对于以修饰的RNA结构为目标的新的可靠和健壮的方法的需求尚未得到满足。这项提案将专注于开发多种化学物质，选择性地针对RNA的修饰，这将提供一个用于追踪表位转录组的合成工具包。易于调节的合成转化的广度和灵活性意味着，RNA修饰中化学特征的内在反应特性可以通过不同的激活模式来利用，这些激活模式旨在安装功能标签或标签，从而通过已建立的方法(如下一代测序)打开检测之门。因此，从新的选择性化学的起点出发，使用全谱不同的化学激活模式的反应设计这一提议将为RNA的化学和生物学方面的新发现打开许多机会。