Animal development requires an extreme amount of precision to properly control gene expression. Mutations that alter the accuracy of these processes result in a variety of human diseases including cancer. The fidelity of development is determined, in part, by turning genes on or off at the right times in relation to the expression of other genes. How this is accomplished at the molecular level remains unknown. Furthermore, our understanding of how these regulatory systems maintain the continuity of developmental processes in constantly changing environmental conditions is limited. The broad goal of this project is to use the C. elegans model system to understand the genetic and molecular mechanisms that mediate precise temporal gene regulation.
Aims outlined in this proposal build from our identification of two conserved proteins, BLMP-1 and LIN-42, that directly control the transcription of key microRNAs mediating stage-specific changes gene expression. In addition to regulating genes that control temporal cell fate specification, we find that these proteins also form the core of a unique Gene Regulatory Network (GRN) that generates oscillatory expression patterns of many additional downstream transcriptional targets. While the BLMP-1/LIN-42 GRN maintains the cyclical expression patterns of its target genes during normal growth, its activity is repressed during acute starvation, a condition where insulin/insulin-like signaling (IIS) systematically arrests development. This GRN is re-engaged when animals resume feeding and is essential for the recovery of normal temporal patterning and cell fate specification after nutrient-dependent arrest. This suggests that the BLMP-1/LIN-42 GRN plays a fundamental homeostatic role that ensures normal patterns of developmental gene expression in diverse environments. Experiments outlined in this proposal will determine the regulatory architecture of this GRN, determine its impact on global gene expression and elucidate the mechanisms by which it maintains the normal expression of key developmental genes in varying environments.
Development is a stepwise process that is, in part, mediated by turning on and off genes at the proper times. Many of the genes that are temporally regulated during development control key processes including cell proliferation and cell fate specification. Mistakes in temporal gene regulation can cause developmental defects and promote the establishment or maintenance of cancer. It is therefore important to understand the regulatory logic and molecular mechanisms that animals use to precisely turn on and off specific genes at the correct times. Experiments outlined in this proposal are geared toward understanding the gene regulatory architectures and conserved cellular machinery that accomplish these tasks. Furthermore, we aim to determine how these components maintain temporal gene expression in diverse environments.
