Chemical Tools for Transcriptome-wide Analysis and Modulation of RNA

ongoing

RNA is an essential biomolecular polymer that exhibits many cellular functions ranging from catalytic to informational that are crucial for life. Long considered as DNA's unexciting counterpart, RNA has in recent years transcended its dull image, driven by pivotal discoveries of its involvement in cellular signalling pathways. Despite the clear importance of RNA in biology and medicine, many of its properties and functions remain elusive. In the RiboChem program we will develop ground-breaking chemical tools for uncovering the identity, function, structure and druggability of RNA on an unparalleled transcriptome-wide level, with a special focus on riboswitches. Riboswitches are structured RNA molecules that have gathered particular interest due to their involvement in bacterial gene regulation that render them attractive targets for antibiotic development. The proposed tools will combine refined chemical design and synthesis, tailored towards RNA's chemical properties, with advanced sequencing technologies. This unique combination enables the discovery of riboswitches throughout the entire transcriptome using a photoaffinity labelling strategy. Customized chemical probes will be used to measure riboswitch conformational dynamics in response to environmental inputs and reveal how bacteria exploit these phenomena to fine-tune their gene expression. Finally, a paradigm-shifting strategy for modulation of riboswitch activity will be developed by applying small molecule covalent modulators of RNA structural elements, which has the potential of transforming the field of RNA targeting. Taken together, the research within RiboChem will find broad applicability in the emerging field of RNA chemistry and biology and help uncover many biological functions and properties of RNA and yield important insight into RNA targeting.