Our lab studies the mechanisms by which cells and organisms respond to genetic change. The genetic landscape faced by a living cell is constantly changing. Developmental transitions, environmental shifts, and pathogenic invasions lend a dynamic character to both the genome and its activity pattern. We study a variety of natural mechanisms that are utilized by cells adapting to genetic change. These include mechanisms activated during normal development and systems for detecting and responding to foreign or unwanted genetic activity. At the root of these studies are questions of how a cell can distinguish self vs. nonself and wanted vs. unwanted gene expression. Studies of silencing have been of value from numerous perspectives. As we understand mechanisms, we generate a significant research toolkit for targeted gene silencing, with considerable hope of extending this to gene-based therapeutics and agricultural biocides. An understanding of gene silencing mechanisms allows us to better design systems for avoiding silencing in cases where expressing specific genes in vivo would be of value. As gene silencing mechanisms are indicative of a variety of cellular gene regulation processes, work on gene silencing has provided valuable insights into normal genetic regulation. Many gene silencing mechanisms reflect the response of the cell/organism to foreign DNA or RNA. Studies of gene silencing can thus extend our understanding and mastery of natural mechanisms used to maintain genome integrity and fight viral infection. Caenorhabditis elegans provides an excellent model for diverse studies of development, physiology, and gene expression, with traditional strengths of the model system in genetic and anatomical analysis combining with a highly-annotated genome and a variety of genetic and epigenetic manipulation techniques. With the variety of tools, information, and experimental questions, this system remains an attractive choice for varied studies of gene expression. C. elegans can be quite proficient at silencing foreign nucleic acid, particularly in the germline; this combined with the other readily manipulated aspects of the system provides an excellent starting point for the study of responses to foreign information. Several questions drive our research program What features mark certain RNAs as self/wanted and others as nonself/unwanted? How is foreign DNA recognized and silenced? How do genomes acquire novel silencing capacities? Can we avoid silencing in experimental/therapeutic protocols aimed at sustained transgene expression? Can we consistently engage silencing to experimentally/therapeutically suppress individual genetic elements?
A greater understanding of signals that activate and silence regions of the genome will illuminate the fundamental mechanisms that our cells use (i) to properly control the activity of each of their genes and (ii) to protect themselves from unwanted genetic activity in the form of viruses and other genomic parasites. This research program applies a variety of information-based and experimental approaches directed toward that understanding.
