The overarching mission of my research program is to elucidate how the ribosomal DNA (rDNA) locus and ribosome biogenesis connect to cellular processes to coordinate complex growth modes during organismal development. The overall objectives of the current proposal are: (1) identification of cell non-autonomous factors that provide a ribosome synthesis checkpoint to control organism-wide growth and (2) investigation of the epigenetic function of nucleolus during organism development. First, we will identify regulators of cell non- autonomous growth arrest in C. elegans by intensive forward genetic screens in strains that produce both wild- type and homozygous ribosomal protein & rDNA null cells in precise lineages. To understand tissue specific contributions to organism-wide growth, we will optimize a system that will reversibly block new ribosome synthesis in a tissue and stage-specific way. Second, we will take advantage of viable C. elegans embryos that lack multi-copy rDNA locus (hence the nucleolus structure) to investigate the fundamental roles of nucleolus in genome organization and gene expression. We will identify and validate nucleolus associated domains. We will then identify the global impact of nucleolus on chromosome architecture, genome organization and gene expression. This study will (1) shed light onto the cell non-autonomous pathways that regulate organism-wide growth coordination and (2) will identify the epigenetic roles of the nucleolus that are distinct from its essential ribosome biogenesis function.
The proposed research will provide fundamental knowledge about the coordination of organism-wide growth during development and the functional role of nucleolus, which is the site of ribosome assembly. Our studies will provide concrete leads towards defining and approaching disease conditions associated with ribosome assembly and translational dysfunction.
