ChemDecEpi: A Chemical Synthesis Approach towards Decoding the Epitranscriptome

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.