The major goal of my research aims to understand a fundamental question in molecular biology relevant to all organisms: how do cells regulate the expression of their genes? Two critical steps in gene expression are 1) transcription, in which RNA is synthesized from DNA (the RNA serves as a “working copy” of the DNA) and 2) RNA splicing, whereby the non-protein-coding introns are removed from RNA by the spliceosome, a large and dynamic enzyme. Splicing must occur efficiently and with single nucleotide precision, or risk the production of non-functional, potentially deleterious proteins. Indeed, mutations in our genes that lead to imprecise RNA splicing underlie numerous human disorders, including cancer. The accuracy of gene expression depends, in part, on effective coordination of RNA splicing with RNA synthesis. Coupling of RNA splicing with transcription provides an opportunity for complex, finely tuned regulation and ensures that only a fully spliced RNA is produced. For example, co-transcriptional recruitment of the RNA splicing machinery allows splicing to commence before transcription is complete, thereby increasing efficiency. Likewise, coupling ensures that splicing does not occur if an error arises that stalls transcription, thus saving valuable energy.
The underlying mechanisms that orchestrate this coordination are poorly defined, but undoubtedly involve specialized proteins that mediate the interaction of RNA molecules with larger protein complexes that synthesize and splice the RNA. Indeed, we recently identified a protein that interacts both with the RNA splicing and transcription machineries to coordinate these two steps in gene expression. My current research involves the combination of genetic, molecular cell biology and biochemical approaches to identify other specialized proteins involved in coupling RNA splicing with transcription. In the future we aim to uncover novel connections between transcription and other critical steps in RNA processing. Because gene expression is a fundamental cellular process, it can be studied in organisms such as the yeast Saccharomyces cerevisiae and give important insight into how the same process functions in humans.