The research of my laboratory aims to discover and characterize fundamental mechanisms that eukaryotes use to organize and maintain their genomes. These investigations focus on the genome-wide, programmed DNA rearrangements of the ciliated protozoan Tetrahymena thermophila, which remodel the developing somatic genome during development. Our work has helped establish that these DNA rearrangements are guided by small RNA-directed heterochromatin formation, which marks a third of the 150 Mbp germline-derived genome for elimination from the differentiating somatic chromosomes. We have identified key proteins that package the DNA to be eliminated into heterochromatin-like bodies and precisely define the boundaries of the excised heterochromatin. In addition, our research has revealed that DNA sequences present in the parental somatic genome, which are not directly inherited by progeny cells, can epigenetically regulate these DNA rearrangements. Our findings provide evidence that these genome-altering events evolved by modifying the roles of existing cellular machineries. Some novel proteins that we have characterized possess structures suggesting a transposon origin, which indicates that the very sequences that these DNA rearrangements target for elimination have, through evolution, contributed to the mechanism of their elimination.
My lab continues to pursues two major research directions. One is to study the RNAi-related mechanism that Tetrahymena cells use to identify the regions of the genome that need to be silenced, directing specific heterochromatin modifications to those sequences during somatic genome differentiation. The other is to characterize the molecular machinery used to package loci into heterochromatin and subsequently eliminate them from the somatic genome. This proposal is based on our recent studies of Lia3, the first protein discovered that regulates the accuracy of DNA elimination. Lia3 binds to a guanine(G)-rich sequence that defines the boundaries of several loci, but only when that sequence forms a G quadruplex structure. We plan to elucidate how distal G-rich sequences can be brought together to form a non-canonical DNA structure that defines heterochromatin domains during development.
While pursuing my research goals, I am committed to training the next generation of scientists at all levels. As a faculty member at Washington University, I have graduated six students from three different programs in the Division of Biology and Biological Sciences, who each earned their PhD’s through research in my laboratory. I currently serve on the steering committees for two graduate programs in: 1) Molecular Genetics and Genomics; and 2) Developmental, Regenerative & Stem Cell Biology and have served as a member of over 40 dissertation advisory committees. As a researcher/educator, I have developed curriculum that engages undergraduates in authentic research in the laboratory classroom. Student generated results have been published in peer-reviewed articles with enrolled students as authors.
I use my time and energy to enhance a larger research community. I serve as a reviewer and/or editor for research journals and as a grant proposal panelist. In addition, I serve as a member of the Tetrahymena Research Advisor Board; I was elected to the inaugural term as President, serving from 2011-2013. The mission of the Board is to increase the impact a research performed using this important model organism. My expertise as a researcher and experience as an educator provide me with important insights that guide my mentorship of students at all levels as they prepare for future careers in science.