Investigating new functions for ancient RNA modifying enzymes in health and disease

RNA modifications are essential for human health—too much or too little leads to serious illnesses ranging from neurodevelopmental disorders to cancer. We are working to uncover the RNA targets of RNA modifying enzymes that are dysregulated in disease and to understand their molecular and organismal roles. Recent advances in detecting the modified nucleoside pseudouridine reveal a complex pseudouridine landscape that includes messenger RNA and diverse classes of noncoding RNA in human cells. The known molecular functions of pseudouridine, which include stabilizing RNA conformations and destabilizing interactions with varied RNA-binding proteins, suggest that RNA pseudouridylation could have widespread effects on RNA metabolism and gene expression. I will give an update on our progress towards answering three questions: What are the molecular consequences of mRNA and non-coding RNA modifications? How do specific defects in RNA metabolism result in organismal phenotypes, including disease? How are RNA sites selected for modification and how is this process regulated?