Diet greatly impacts metabolism in health and disease. In response to the presence or absence of specific nutrients, metabolic gene regulatory networks sense the metabolic state of the cell and regulate metabolic flux accordingly, for instance by the transcriptional control of metabolic enzymes. Here, we discuss recent insights regarding metazoan metabolic regulatory networks using the nematode Caenorhabditis elegans as a model, including the modular organization of metabolic gene regulatory networks, the prominent impact of diet on the transcriptome and metabolome, specialized roles of nuclear hormone receptors (NHRs) in responding to dietary conditions, regulation of metabolic genes and metabolic regulators by miRNAs, and feedback between metabolic genes and their regulators.
Walhout lab graduate student Emma Watson received the 2014 Harold M. Weintraub Graduate Student Award for research into the complex interactions between diet, gene expression and physiology. Only 13 students from North America were chosen for the prestigious award sponsored by the Basic Sciences Division of the Fred Hutchinson Cancer Research Center. Fellow UMass graduate student Colin Conine who studies in Craig Mello’s lab also received the Weintraub award.
“I’m happy that both Colin and I won the award this year. I think it’s a testament to the strong community of C. elegans biologists here at UMass Medical School, with whom we have both trained,” said Watson. “We use the roundworm C. elegans to explore basic biological processes and find new angles of attack for human disease. C. elegans was the perfect model for me to study the genetic underpinnings that link diet and physiology. Its metabolic network and nutritional requirements are surprisingly a lot like ours, despite being a soil-dwelling nematode that eats bacteria all day long!”
“Emma is an outstanding graduate student who fully deserves this award,” said Dr. Walhout. “It is a pleasure to work with her. She is hard working, smart, fun and has vision. If she sets the bar, it is very high!”
Watson focuses her research on understanding the effects of diet on the genome, and how this relates to physiology. Using C. elegans and its bacterial diet, Watson developed a novel interspecies model that allows these questions to be addressed systemically. With this new systems biology model, she found that worms fed a diet of vitamin-B12-synthesizing bacteria exhibit altered gene expression and accelerated development compared to worms fed bacteria that cannot synthesize vitamin B12. Watson also found that worms rewire their metabolic network according to B12 availability, especially with regard to propionic acid metabolism, which depends on this essential vitamin and can cause a buildup of toxic metabolites under B12 deficiency.
The Weintraub award, established in 2000, honors the late Harold “Hal” M. Weintraub, PhD, a founding member of Fred Hutchinson’s Basic Sciences Division, who died of brain cancer in 1995 at age 49. Weintraub was an international leader in the field of molecular biology. Among his many contributions, he identified genes responsible for instructing cells to differentiate, or develop, into specific tissues such as muscle or bone. The award honors Weintraub and his enthusiastic support of colleagues, students and young scientists.
Conine and Watson will participate in a scientific symposium on May 2 at Fred Hutchinson Cancer Research Center in Seattle.
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.
GAIN: Guide for Association Index for Networks website
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