ChemDecEpi: A Chemical Synthesis Approach towards Decoding the Epitranscriptome

除了储存在RNA序列中的核心信息之外，第二层编程以对规范核碱基进行大量化学修饰的形式存在。在RNA中已经发现了超过140种不同的变异。这些转录后修饰的核糖核苷酸在基因中编码的信息的细胞控制中起着不可或缺的作用，并且在所有RNA类型中普遍存在，并且统称为表转录组。除了普遍存在外，RNA修饰也是保守的，对生物学的许多方面至关重要，并被认为影响了大约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位转录组。目前，大多数用于检测修饰的RNA的方法使用对特定修饰具有选择性的抗体。虽然存在许多变化，但它们并不总是提供一般意义上的单核苷酸分辨率，并且仅存在少数RNA修饰，因此许多修饰的核糖核苷酸对于这些检测技术是不可见的。对于靶向修饰的RNA结构的新的可靠且稳健的方法存在未满足的需求。该提案将专注于开发选择性靶向RNA修饰的多种化学物质，这将提供一种用于跟踪表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修饰中化学特征的固有反应特性可以通过设计用于安装功能性标记或标签的不同激活模式来利用，从而打开了通过诸如下一代测序的已建立方法进行检测的大门。因此，从新的选择性化学出发，使用全谱不同的化学活化模式进行反应设计，这一提议将为RNA化学和生物学的新发现开辟许多机会。

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.