Genetic and Genomic Regulation of Starvation Response

Abstract

This dissertation examines how Caenorhabditis elegans adapts to changes in nutrient availability by modulating diverse signaling and gene regulatory networks. Focusing on L1 arrest—a diapause state characterized by paused development and a profoundly reprogrammed transcriptome—this work dissects the regulatory circuits governing starvation resistance. Across five interrelated projects, we employed a combination of genetic, genomic, biochemical, proteomic, and molecular biology approaches—including epistasis analysis, single-cell RNA-sequencing (scRNA-seq), immunoprecipitation (IP), massspectrometry (MS), and single-molecule fluorescence in situ hybridization (smFISH), complemented by bioinformatic analyses. Our studies reveal that conserved signaling pathways, including insulin/IGF-1 (IIS) and MEK/ERK signaling, together with critical transcriptional regulators such as daf-16/FoxO and the DREAM complex, orchestrate the starvation response. In particular, DAF-18/PTEN emerges as a central regulator whose dual phosphatase activities are pivotal for maintaining cellular quiescence and protecting the tumor suppressor LIN-35/Rb. Additionally, our investigations into mpk-1/ERK underscore the importance of its zygotic, somatic, doubly phosphorylated form for starvation resistance, while our characterization of ist-1/IRS1 highlights its role in transducing IIS signals. Importantly, our single-cell transcriptomic analysis reveals extensive tissue-specific reprogramming during starvation, including an unexpected upregulation of aak-1/AMPK in primordial germ cells (PGCs)—a response essential for preserving chromatin integrity and ensuring fertility upon recovery. Together, this dissertation provides a comprehensive conceptual framework for understanding how genetic and genomic mechanisms orchestrate starvation resistance, with broader implications for tumor suppression, energy homeostasis, and aging.