RNA carries chemical tags that alter how genes are read, and scientists lack reliable tools to detect most of them. More than 140 distinct chemical modifications have been found on RNA molecules, yet current detection methods rely on antibodies that work for only a handful of these tags and often fail to pinpoint their exact location. This leaves the vast majority of RNA modifications invisible to researchers, even though they are thought to influence roughly 16,000 human genes. The problem is that no general, single-nucleotide-resolution technique exists for mapping the epitranscriptome—the full set of RNA modifications in a cell. This project aims to build a synthetic chemistry toolkit that selectively targets specific RNA modifications. By designing chemical reactions that exploit the unique reactive properties of each modification, the researchers will install detectable labels that can be read by standard sequencing technologies. If successful, the approach would open up the entire epitranscriptome to systematic study. The work is fundamental science. It does not promise an immediate medical or industrial application. But understanding how RNA modifications control gene expression could eventually illuminate mechanisms behind diseases such as cancer and neurological disorders, where these chemical tags are known to go awry.
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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.
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