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Research Statement
We develop new experimental methods for studying the genomics of gene regulation, making extensive use of second-generation DNA sequencing and computational biology.

Active areas of interest include:

Regulatory DNA and nuclear architecture
With collaborators at the University of Washington, we developed a method combining DNase I digestion of yeast chromatin with second-generation DNA sequencing for the direct identification of protein-DNA interactions on a genome-wide scale (Hesselberth et al, 2009). Analysis of 23 million DNase I cleavages across 80% of the genome revealed thousands of DNA protection patterns caused by protein binding (i.e. “footprints”) with base-pair resolution, as well as large-scale features of chromosome structure (e.g. nucleosome positions). We showed that this method is complementary to existing ChIP-chip data, indicating that it has the potential to expose the cis-regulatory framework of any organism with an available genome sequence in a single experiment. In the future, we will adapt this method to study the evolution of DNA regulatory mechanisms in multiple yeast species.

Genome-scale identification of RNA secondary structure and RNA-protein interactions
Unlike the double-helical DNA templates from which they are expressed, RNA transcripts fold into unique secondary structures that are specified by their sequences. Unfortunately, current genome-scale methods for studying RNA transcripts fail to capture the structural complexity of these transcripts in vivo. To catalyze a new understanding of functional RNA structure, we are developing an approach to analyze in vivo RNA secondary structure and RNA-protein interactions on a genomic scale. The method, based on our previous work with genome-scale DNA footprinting, would be capable of characterizing RNA structure in any organism with an available genome sequence, providing an unprecedented view of RNA sequence-structure relationships at base-pair resolution. This method will position cis-regulatory sites within their structural contexts and will identify sites of RNA-protein interaction. Ultimately, it will support a new theoretical framework for integrating RNA sequence-structure relationships, and its application should guide the design of new RNA-based therapeutics.

Discovery and characterization of novel RNA elements
We are generally interested in the development of new methods for studying cellular RNA populations. Recently, we developed a method for the capture and sequencing of RNAs with terminal 2’,3’-cyclic phosphates (Schutz et al., submitted). Cyclic phosphate-terminated RNAs are generated by endonucleolytic cleavage and self-cleaving ribozymes, and are found as stable modifications on cellular RNAs such as the U6 spliceosomal RNA. We applied the method to identify specific cleavages in transfer RNAs, and preliminary experiments suggest that the method can identify previously unrecognized cleavage events in human mRNAs. Because the method employs a ligase with unique specifiity, it can identify RNA subtypes previously undetected by other RNA cloning techniques.​​​​