Project description:The molecular mechanisms underlying the physiological and cellular response to starvation are still not fully understood. We have used quantitative proteomics and RNA-seq to examine the temporal responses to starvation in the multicellular organism C. elegans, comparing the response in both wild type animals and in animals lacking the transcription factor HLH-30. Our findings show that starvation alters the abundance of hundreds of proteins and mRNAs in a temporal manner, many of which are involved in central metabolic pathways including lipoprotein metabolism. We show that hlh-30 animals die prematurely when starved, which can be prevented by knockdown of either vit-1 or vit-5, encoding two different lipoproteins. We show that the size and number of intestinal lipid droplets under starvation are altered in hlh-30 animals, that can be rescued by knockdown of vit-1, indicating that rescue of survival of hlh-30 animals under starvation conditions is closely linked to the size and number of intestinal lipid droplets.
Project description:How animals coordinate gene expression in response to starvation is an outstanding problem closely linked to aging, obesity, and cancer. Newly hatched Caenorhabditis elegans respond to food deprivation by halting development and promoting long-term survival (L1 diapause), thereby providing an excellent model to study starvation response. Through a genetic search, we have discovered that the tumor suppressor Rb critically promotes survival during L1 diapause and likely does so by regulating the expression of genes in both insulin-IGF-1 signaling (IIS)-dependent and -independent pathways mainly in neurons and the intestine. Global gene expression analyses suggested that Rb maintains the “starvation-induced transcriptome” and represses the “re-feeding induced transcriptome”, including the repression of many pathogen/toxin/oxidative stress-inducible and metabolic genes, as well as the activation of many other stress-resistant genes, mitochondrial respiratory chain genes, and potential IIS receptor antagonists. Notably, the majority of genes dysregulated in starved L1 Rb(-) animals were not found to be dysregulated in fed conditions. Together, these findings identify Rb as a critical regulator of the starvation response and suggest a link between functions of tumor suppressors and starvation survival. These results may provide mechanistic insights into why cancer cells are often hypersensitive to starvation treatment.
