Diet greatly influences gene expression and physiology. In mammals, elucidating the effects and mechanisms of individual nutrients is challenging due to the complexity of both the animal and its diet. Here, we used an interspecies systems biology approach with Caenorhabditis elegans and two of its bacterial diets, Escherichia coli and Comamonas aquatica, to identify metabolites that affect the animal’s gene expression and physiology. We identify vitamin B12 as the major dilutable metabolite provided by Comamonas aq. that regulates gene expression, accelerates development, and reduces fertility but does not affect lifespan. We find that vitamin B12 has a dual role in the animal: it affects development and fertility via the methionine/S-Adenosylmethionine (SAM) cycle and breaks down the short-chain fatty acid propionic acid, preventing its toxic buildup. Our interspecies systems biology approach provides a paradigm for understanding complex interactions between diet and physiology.
Watson E, MacNeil LT, Ritter AD, Yilmaz LS, Rosebrock AP, Caudy AA, Walhout AJ. (2014) Interspecies systems biology uncovers metabolites affecting C. elegans gene expression and life history traits. Cell. 156:759-70. PubMed, Cell
Gene expression is controlled through the binding of transcription factors (TFs) to regulatory genomic regions. First introns are longer than other introns in multiple eukaryotic species and are under selective constraint. Here we explore the importance of first introns in TF binding in the nematode Caenorhabditis elegans by combining computational predictions and experimentally derived TF-DNA interaction data. We found that first introns of C. elegans genes, particularly those for families enriched in long first introns, are more conserved in length, have more conserved predicted TF interactions and are bound by more TFs than other introns. We detected a significant positive correlation between first intron size and the number of TF interactions obtained from chromatin immunoprecipitation assays or determined by yeast one-hybrid assays. TFs that bind first introns are largely different from those binding promoters, suggesting that the different interactions are complementary rather than redundant. By combining first intron and promoter interactions, we found that genes that share a large fraction of TF interactions are more likely to be co-expressed than when only TF interactions with promoters are considered. Altogether, our data suggest that C. elegans gene regulation may be additive through the combined effects of multiple regulatory regions.
Fuxman Bass JI, Tamburino AM, Mori A, Beittel N, Weirauch MT, Reece-Hoyes JS, Walhout AJ. (2014) Transcription factor binding to Caenorhabditis elegans first introns reveals lack of redundancy with gene promoters. Nucleic Acids Res. 42:153-62. PubMed, Full Text, Nucleic Acids Res.
C. elegans, both in the wild and in the lab, live on a diet of live bacteria. The bacterial diet provides nutrients for C. elegans, but can also play a number of other roles in C. elegans physiology. Recently, we compared the effects of different bacterial diets on life history traits and gene expression. Here, we discuss our recent findings in the context of other dietary studies and highlight challenges in understanding dietary effects. For instance, since bacteria can be pathogenic it can be difficult to disentangle pathogenic from dietary effects. Here we summarize different bacterial diets used for C. elegans and how they affect the animal.
Macneil LT, Walhout AJ. (2013) Food, pathogen, signal: The multifaceted nature of a bacterial diet. Worm. 2:e26454. PubMed, Full Text, Worm
Biological networks can be used to functionally annotate genes on the basis of interaction-profile similarities. Metrics known as association indices can be used to quantify interaction-profile similarity. We provide an overview of commonly used association indices, including the Jaccard index and the Pearson correlation coefficient, and compare their performance in different types of analyses of biological networks. We introduce the Guide for Association Index for Networks (GAIN), a web tool for calculating and comparing interaction-profile similarities and defining modules of genes with similar profiles.
Fuxman Bass JI, Diallo A, Nelson J, Soto JM, Myers CL, Walhout AJ. (2013) Using networks to measure similarity between genes: association index selection. Nat Methods. 10:1169–1176. Erratum in: Nat. Methods. 11:349. PubMed, Full Text, Nat. Methods
Gene duplication results in two identical paralogs that diverge through mutation, leading to loss or gain of interactions with other biomolecules. Here, we comprehensively characterize such network rewiring for C. elegans transcription factors (TFs) within and across four newly delineated molecular networks. Remarkably, we find that even highly similar TFs often have different interaction degrees and partners. In addition, we find that most TF families have a member that is highly connected in multiple networks. Further, different TF families have opposing correlations between network connectivity and phylogenetic age, suggesting that they are subject to different evolutionary pressures. Finally, TFs that have similar partners in one network generally do not in another, indicating a lack of pressure to retain cross-network similarity. Our multiparameter analyses provide unique insights into the evolutionary dynamics that shaped TF networks.
Reece-Hoyes JS, Pons C, Diallo A, Mori A, Shrestha S, Kadreppa S, Nelson J, Diprima S, Dricot A, Lajoie BR, Ribeiro PS, Weirauch MT, Hill DE, Hughes TR, Myers CL, Walhout AJ. (2013) Extensive rewiring and complex evolutionary dynamics in a C. elegans multiparameter transcription factor network. Mol. Cell 51:116-27. PubMed, Full Text, Mol. Cell
On the cover: The kind of food an organism consumes has a broad reaching impact on its development, behavior, and lifespan. In this issue, two papers, MacNeil et al. (pp. 240–252) and Watson et al. (pp. 253–266), explore the effects of diet on these life-history traits in the nematode C. elegans. Combining nutrigenomics and network analyses, they find that different diets affect traits via distinct mechanisms. The response to diet is coupled to metabolic changes, and disruptions of some of these specific metabolic pathways correspond to inborn errors of metabolism in humans. The cover features a “native-art-inspired abstraction” of a worm eating a bacterial diet and illustrates the interconnectedness between diet, nuclear gene regulatory networks, mitochondrial networks, and their effects on life-history traits such as development and brood size. Cover art by Lesley T. MacNeil.
Expression profiles are tailored according to dietary input. However, the networks that control dietary responses remain largely uncharacterized. Here, we combine forward and reverse genetic screens to delineate a network of 184 genes that affect the C. elegans dietary response to Comamonas DA1877 bacteria. We find that perturbation of a mitochondrial network composed of enzymes involved in amino acid metabolism and the TCA cycle affects the dietary response. In humans, mutations in the corresponding genes cause inborn diseases of amino acid metabolism, most of which are treated by dietary intervention. We identify several transcription factors (TFs) that mediate the changes in gene expression upon metabolic network perturbations. Altogether, our findings unveil a transcriptional response system that is poised to sense dietary cues and metabolic imbalances, illustrating extensive communication between metabolic networks in the mitochondria and gene regulatory networks in the nucleus.
Watson E, MacNeil LT, Arda HE, Zhu LJ, Walhout AJ. (2013) Integration of metabolic and gene regulatory networks modulates the C. elegans dietary response. Cell, 153:253-266. PubMed, Full Text, Cell