The Chemical Biology of Large-Scale Transcriptome Analysis

Most RNAs rapidly fold back on themselves to form numerous functionally important, but difficult to predict and largely uncharacterized, base paired and higher order structures. Our laboratory is blending new RNA chemistries, largely directed at the ribose 2'-hydroxyl group, with quantitative interpretation to make possible facile and highly accurate RNA structure analysis. This approach melds the methods of physical and mechanistic biochemistry, chemical biology, virology and microbiology, and bioinformatics. We then apply these technologies to important, and otherwise intractable, problems in biology. With collaborators at UNC and the National Cancer Institute, we have developed a working model for the architecture of an entire HIV-1 genome. This secondary structure model represents, in essence, a diverse set of hypotheses for how RNA structure governs viral replication. Recent functional studies supporting many of these structural hypotheses will be emphasized.