Deciphering the Role of lncRNAs as Scaffolds that Coordinate Cellular Regulation
It is now clear that mammalian genomes encode many thousands of large non-coding RNAs (lncRNAs). These lncRNAs play critical roles in diverse biological processes including in the control of cell-state decisions. Many lncRNAs physically interact with multiple distinct chromatin regulatory proteins that are important for gene regulation. These results suggest that lncRNAs may act as scaffolds of regulatory proteins to create unique regulatory complexes that coordinate their precise cellular functions. The presence of many thousands of lncRNAs that can scaffold distinct regulatory protein complexes may explain the coordination of different regulatory proteins in different cellular conditions and how improper regulation of a lncRNA may give rise to human disease.
While this model is attractive, it remains largely untested. To date, we still do not know the protein complexes that interact with lncRNAs, how lncRNAs integrate proteins into larger macromolecular complexes, and how these interactions control cellular functions. To address these questions, we will develop novel methods to comprehensively define the protein complexes associated with a lncRNA. Using these methods, we will identify the protein complexes that interact with a lncRNA, determining where these protein interactions occur on the lncRNA, and explore the dynamics of lncRNA-mediated macromolecular complex assembly across cellular conditions. We will probe the function of these lncRNA complexes by generating precise genetic mutants that impact binding of individual protein complexes to understand how a lncRNA can integrate distinct proteins to coordinate cellular functions.
This research will provide important insights into how lncRNAs bridge distinct protein complexes to assemble cell-type specific macromolecular complexes that orchestrate cellular regulation. The results of this study will provide an understanding of the principles governing lncRNA-complex assembly and function in cellular regulation and provide a framework for understanding how mutations in individual lncRNA domains may lead to human disease.