Quantitative and mechanistic dissection of messenger RNA stability

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RNA molecules can differ substantially in their stability, which directly impacts their function, e.g., through regulating the amount of protein produced by mRNAs. How the stability of long RNAs is determined via an interplay of sequence, chemical modifications, structure, and RNA binding proteins (RBPs), and how this varies depending on the origin of the RNA remains poorly understood. Understanding the codes determining RNA stability is key for understanding how regulation of gene expression is redirected in diverse physiological and pathological contexts, including development, infectious disease, and tumors. It is also important for effective design of new RNA therapies and for understanding which mutations in mRNAs and lncRNAs can have detrimental consequences. The m6A RNA modification, which is installed during transcription has recently emerged as a major determinant of RNA stability, with additional determinants set by RNA binding proteins (RBPs), andothers remaining unclear, in particular for RNAs that are are not produced in the nucleus. In this interdisciplinary joint proposal, we aim to quantitatively, functionally, biochemically, and structurally dissect how sequence elements, chemical modifications, structure and RBPs impact mRNA stability. It synergizes state-of-the art high-throughput RNA assays and computational biology (expertise provided by the Ulitsky and Schwartz labs), with cutting-edge biochemical and structural approaches (provided by the Meister and Fischer labs), to unravel how sequence, processing, mRNA modifications and RBPs synergize to dictate mRNA stability. Together, these studies will provide a detailed mechanistic understanding of the cis and trans determinants dictating the mRNA life cycle. Our investigations will also be highly valuable for developing novel RNA technologies relevant for biomedicine and beyond.