Abstract/Summary (Andrew Fire PI, NIGMS R35GM130366, January 2023) 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. 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 allow certain RNAs to persist and propagate without encoding a replication machinery? In what circumstances are non-chromosomal inheritance processes utilized by biological systems? How do machineries that propagate non-chromosomal inheritance serve the organism? Can we adapt the underlying persistence mechanisms for experimental/therapeutic protocols aimed at sustained expression or sustained suppression?