Functional RNA elements in the human genome

About This Grant

PROJECT SUMMARY/ABSTRACT At all points in their life cycle, RNA molecules are bound and regulated by RNA-binding proteins (RBPs), which play important roles in RNA splicing, subcellular localization, translation, and degradation. Annotated RBPs comprise an estimated ~5-8% of all protein-coding genes; however, results from RBP experimental studies and our computational predictions suggest that the true number of RBPs is much higher, by some estimates representing up to one-third of the cellular proteome and thus including thousands of uncharacterized RBPs. In the previous grant cycle, we have generated critical experimental technologies, data resources and computational tools that we now leverage to comprehensively study the role of thousands of predicted and known RBPs in RNA processing and cellular function. We will perform tethered function reporter assays at scale and single-cell based studies to identify RBPs with previously unknown functions in RNA stability, alternative polyadenylation and translation. We will also deeply characterize the RNA targets and target recognition mechanisms of the large class of zinc finger domain-containing RBPs that hold promise as novel tools in basic research and as fundamentally new therapeutic systems for many diseases. Lastly, rapid progress in machine learning and large language models have profoundly advanced our understanding of genomics and proteomics, leveraging artificial intelligence to decode complex patterns in amino acid sequences to predict protein structure and function, and have proven to be invaluable resources in studying both protein structure and protein-based therapies. Utilizing these emerging computational technologies, we develop a large language model focused on RNA instead of protein decipher the regulatory mechanisms of RNA dynamics. If successful, we will generate the first map of TNA processing pathways that will ultimately enable trajectories of RNA fate to be predicted by RNA sequence alone.