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 developmental gene regulation is determined, in part, by turning genes on or off at the right times in relation t the expression of other genes. How this is accomplished at the molecular level remains unknown. Furthermore, our understanding about how the regulatory systems that maintain the continuity of developmental process in constantly changing environmental conditions is limited. The proposed studies seek to determine how oscillatory patterns of gene expression confer stability to developmental systems. This knowledge will provide the opportunity to determine if perturbations of this system are linked to disease and may offer potential prospects for intervention. 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, which generate oscillatory expression patterns of downstream target genes (including microRNAs that dictate cell fate specification) and couples these patterns of expression to the molting cycles of post-embryonic development. Experiments outlined in this proposal will determine how this system generates these patterns of expression and tunes microRNA expression levels to maintain homeostasis of temporally regulated genes. In addition, we will determine how this unique regulatory module becomes essential for miRNA gene regulation and the reprograming of temporal patterning when nutrient depravation triggers developmental arrest. Molecular and genetic approaches will be employed to determine the regulatory underpinnings of this system, to define the pervasiveness of temporally dynamic gene expression, and to determine what portions of this regulatory architecture are dependent on blmp-1 and lin-42.
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 common themes 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.
