Chemical Microscopes for High-Content RNA Structure Analysis
A guiding vision of research in the Weeks group is to apply chemical principles to create high-content molecular microscopes to understand the function of the three-dimensional folding of RNA in cells and viruses. This work addresses multiple, critical challenges in cellular and structural biology because RNA functions as the central conduit for biological information transfer, yet we understand very little about the global architecture and molecular mechanisms of most RNAs.
This work lies at the interfaces of multiple fields – the fundamental chemical sciences, applied to RNA; high-throughput and high-content technology development that melds biophysical and organic chemistry, computational biology, bioinformatics, and chemical and structural biology; and applications to virology, molecular pathogenesis, and cell biology.
Laboratory projects ultimately lead to deeply practical applications in virology, next-generation structure analysis, drug discovery, and understanding biological processes in living cells. SHAPE technologies for interrogating RNA structure at nucleotide resolution – invented and under on-going development in the laboratory – are in use worldwide.
Structure and Function in the Transcriptome
In their roles critical for essentially every step of gene expression, most RNAs fold back on themselves to form specific, dynamic, and complex three-dimensional structures. Until recently, is has been very difficult to understand these underlying structure-function interrelationships because we simply could not measure long-range structural features of RNA.
Our second vision is thus to use the high-content, genome-scale technologies invented in our laboratory to study complex RNA-based systems that play pivotal roles in cellular function and human disease. Recent work has addressed basic science challenges of how RNA folds and has resulted in development of concise approaches for accurately determining the structure of large RNAs. We also address immediately practical challenges and have, for example, identified highly potent inhibitors of HIV-1 and shown how the genetic code can be expressed through RNA structure.
Significant work focuses on the genome structure of RNA viruses, especially HIV-1, because RNA genomes are elegant (and terrible) usurpers of cellular metabolism, yet are simple enough to be understood at a high level of detail. We also study the functions of biomedically important RNA-protein complexes inside living cells and discovery of small-molecule ligands that target medically important RNAs.