The goal of this project is to understand how ribonucleic acid (RNA) chemistry affects fundamental biological processes. Recent evidence has indicated that enzyme-installed modifications on RNA can regulate how genes are expressed in cells; however, there are major gaps in our understanding of this phenomenon, including which RNA molecules are modified, which enzymes catalyze the modifications, and how these modifications affect RNA function. This project seeks to address these questions through the application of innovative approaches integrating chemistry and biology, and will provide unique training opportunities for students at the interface of these disciplines. The research is also combined with an education and outreach plan aimed at broadening secondary school and undergraduate level engagement with nucleic acid chemistry and biology. These efforts will include the development of a video-based series aimed at disseminating landmark results in the primary scientific literature to New Jersey high school students.

Epitranscriptomic modifications on eukaryotic mRNA have been implicated in gene expression regulation. In particular, a diverse set of chemical modifications of cytosine are known to exist in mRNA, but a definitive understanding of the distribution of these marks, the enzymes that mediate their installation, and ultimately their biological function, is lacking. This project aims to address these questions by developing metabolically-incorporated chemical probes to capture RNA cytosine-modifying enzyme activity in cells. The probes will be integrated with proteomic and transcriptomic workflows and genetic perturbations in order to profile relevant RNA modifying enzymes, map their cellular substrates, identify reader proteins, and interrogate the functional consequences of cytosine modifications on mRNA behavior. Together, these research approaches will reveal insights into the regulation of cellular RNA through enzymatic modification and provide powerful tools for probing RNA modifications in diverse biological contexts.

This project is jointly funded by the Genetic Mechanisms cluster in the Molecular and Cellular Biosciences Division, and the Chemistry of Life Processes program in the Chemistry Division.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

National Science Foundation (NSF)
Division of Molecular and Cellular Biosciences (MCB)
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Manju Hingorani
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Princeton University
United States
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