Zachary Harvey
In the broadest possible sense, I am interested in questions of how eukaryotic life became so complex, and what this complexity means for how organisms evolve. In pursuit of this aim, I study chromatin––the complex of protein and DNA essential to genome function––to understand the fundamental molecular mechanisms shaping its evolution. I combine quantitative methods from synthetic and chemical biology with insights garnered from molecular evolution, developing new tools and approaches to address questions in in two broad areas:
Using evolutionary diversity to understand histone function. Over eukaryotic evolution, histones, the basic building block of chromatin, have diverged to give rise to dozens of new variant forms with distinct functions. Most of these histone variants have yet unknown molecular mechanisms. Using the fission yeast Schizosaccharomyces pombe as a platform to assay extant histone sequences taken from across the entire eukaryotic tree, I am exploring how sequence variation, rather than conservation, shapes histone function. With support from the FWF ESPRIT program, I am uncovering how sequence variation in one histone variant, H2A.Z, changes its function in transcription. H2A.Z is present in essentially every eukaryote, yet its function has remained enigmatic. Using synthetic and high-throughput quantitative genetic approaches, I am working to resolve this decades-long question, giving us new insights into the fundamental mechanisms of chromatin and transcription.
Mapping chromatin dynamics in time and space at near single-nucleotide resolution. A major challenge to understanding the fundamental mechanisms regulating chromatin is that current genomic technologies only look at steady-state conditions and are unable to capture highly dynamic events in the cell. To address this, I have developed a new technology to accurately and with near base-pair resolution profile chromatin-binding proteins. I am currently using this technology to generate genome-wide maps of factors such as SWI/SNF proteins, which were previously inaccessible using existing technologies. With these insights, I aim to ascribe molecular functions to the dozens of largely uncharacterized remodelers, as well as other chromatin-associated proteins.