Expression data from the starved first larval stage (L1) C. elegans animals that were incubated in S-basal buffer for 30 hours after bleaching

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.

RNA interference and retinoblastoma related genes are required for repression of endogenous siRNA targets in C. elegans

Expession data from L1-L2 stage nematodes (C. elegans), wild type and four mutants (alg-1, zfp-1, rde-4, lin-35). In C. elegans, a vast number of endogenous short RNAs corresponding to thousands of genes have been discovered recently. This finding suggests that these short interfering RNAs may contribute to regulation of many developmental and other signaling pathways in addition to silencing viruses and transposons. Based on this microarray analysis of gene expression in RNA interference (RNAi)-related mutants rde-4, zfp-1 and alg-1 and the Retinoblastoma (Rb) mutant lin-35, we found that a component of Dicer complex RDE-4 and a chromatin-related zinc finger protein ZFP-1, not implicated previously in endogenous RNAi, regulate overlapping sets of genes. Notably, genes a) upregulated in the rde-4 and zfp-1 mutants and b) upregulated in the lin-35(Rb) mutant, but not the downregulated genes are highly represented in the set of genes with corresponding endogenous short interfering RNAs (endo-siRNAs). Keywords: wildtype-mutant comparison, RNAi, Rb, endo-siRNA

Expression data from starved first larval stage of wildtype and hyl-1(ok976); lagr-1(gk327) C. elegans

Our understanding of cellular mechanisms by which animals regulate their response to starvation is limited despite the close relevance of the problem to major human health issues. L1 diapause of Caenorhabditis elegans, where newly hatched first stage larval arrested in response to food-less environment, is an excellent system to study the problem. We found through genetic manipulation and lipid analysis that ceramide biosynthesis, particularly those with longer fatty acid side chains, critically impacts animal survival during L1 diapause. Genetic and expression analyses indicate that ceramide likely regulate this response by affecting gene expression and activity in multiple regulatory pathways known to regulate starvation-induced stress, including the insulin-IGF-1 signaling (IIS) pathway, Rb and other pathways that mediate pathogen/toxin/oxidative stress responses. These findings provide an important insight into the roles of sphingolipid metabolism in not only starvation response but also aging and food-response related human health problems.