The Structure, Function and Evolution of Biological Networks
1: Gene Regulatory Networks
2: Regulation of Metabolic Networks
1: Gene Regulatory Networks
2: Regulation of Metabolic Networks
Our body is inhabited by a large community of microorganisms referred to as our microbiota that influences almost all aspects of human physiology, including the response to thereapeutic drugs. Drugs can affect microbiota composition and the microbiota can modulate the drug response in the host. A major challenge is to determine which bacteria affect the response to which drugs, and to elucidate the mechanisms involved. Here, we discuss the emergence of the nematode Caenorhabditis elegans and its bacterial diet as an interspecies model system with which the effects of bacteria on the drug response in the host can be studied both at broad systems and at deep mechanistic levels. We will discuss the strengths and limitations of this system and will present future perspectives.
Diot C, Garcia-Gonzalez AP, Walhout AJM (2019). C. elegans and its bacterial diet: An interspecies model to explore the effects of microbiota on drug response. Drug Discovery Today: Disease Models.
Iron is an essential micronutrient for all forms of life; low levels of iron cause human disease, while too much iron is toxic. Low iron levels induce reactive oxygen species (ROS) by disruption of the heme and iron-sulfur cluster-dependent electron transport chain (ETC). To identify bacterial metabolites that affect development, we screened the Keio Escherichia coli collection and uncovered 244 gene deletion mutants that slow Caenorhabditis elegans development. Several of these genes encode members of the ETC cytochrome bo oxidase complex, as well as iron importers. Surprisingly, either iron or anti-oxidant supplementation reversed the developmental delay. This suggests that low bacterial iron results in high bacterial ROS and vice versa, which causes oxidative stress in C. elegans that subsequently impairs mitochondrial function and delays development. Our data indicate that the bacterial diets of C. elegans provide precisely tailored amounts of iron to support proper development.
Zhang J, Li X, Olmedo M, Holdorf AD, Shang Y, Artal-Sanz M, Yilmaz LS, Walhout AJM. (2019). A Delicate Balance between Bacterial Iron and Reactive Oxygen Species Supports Optimal C. elegans Development. Cell Host Microbe.
Congratulations to Dr. Aurian P. Garcia-Gonzalez on successfully defending her doctoral dissertation titled, “C. elegans as a model for host-microbe-drug interactions.” Dr. Garcia-Gonzalez will return to medical school next month, and will complete her MD degree in 2021. Great job Auri!
Metabolic reactions form the basis of life to generate biomass, produce energy and eliminate waste. Together, metabolic reactions function in the context of a highly interconnected metabolic network. Flux through this network needs to be adaptable depending on nutrient availability or metabolite buildup. Metabolic flux can be changed by different regulatory mechanisms, including the allosteric regulation of metabolic enzyme activity by small molecules, and by changes in metabolic gene expression. For the transcriptional control of metabolic genes to happen accurately, the metabolic status of the system needs to be relayed to the regulators of gene expression, such as transcription factors (TFs). While allosteric regulation of metabolic enzymes can only be studied for individual proteins, the transcriptional control of metabolism can increasingly be examined at a systems, or network level. Here, we discuss recent studies regarding the interplay between metabolic and gene regulatory networks using the nematode Caenorhabditis elegans. We discuss why C. elegans provides an elegant model system for studying the transcriptional regulation of metabolism and describe recent insights into its gene regulatory and metabolic networks. We then describe a recently discovered mechanism by which the buildup of a cellular metabolite can transcriptionally rewire metabolism. Finally, we discuss the future challenge of integrating large transcriptomic, proteomic and metabolomic datasets to fully understand the transcriptional regulation of metabolic flux.
Giese GE, Nanda S, Holdorf AD, Walhout AJM. (2019) Transcriptional regulation of metabolic flux: a C. elegans perspective. Curr Opin Syst Biol 15, 12-18.
Biological systems must possess mechanisms that prevent inappropriate responses to spurious environmental inputs. Caenorhabditis elegans has two breakdown pathways for the short-chain fatty acid propionate: a canonical, vitamin B12-dependent pathway and a propionate shunt that is used when vitamin B12 levels are low. The shunt pathway is kept off when there is sufficient flux through the canonical pathway, likely to avoid generating shunt-specific toxic intermediates. Here, we discovered a transcriptional regulatory circuit that activates shunt gene expression upon propionate buildup. Nuclear hormone receptor 10 (NHR-10) and NHR-68 function together as a “persistence detector” in a type 1, coherent feed-forward loop with an AND-logic gate to delay shunt activation upon propionate accumulation and to avoid spurious shunt activation in response to a non-sustained pulse of propionate. Together, our findings identify a persistence detector in an animal, which transcriptionally rewires propionate metabolism to maintain homeostasis.
Bulcha JT, Giese GE,Ali MZ, Lee Y-U, Walker MD, Holdorf AD, Yilmaz LS, Brewster RC, Walhout AJM. (2019) A Persistence Detector for Metabolic Network Rewiring in an Animal. Cell Reports 26, 460-468.
Dr. Walhout provides perspective in the April 20 issue of Science on the latest Research Article from a longstanding collaboration between Brenda Andrews and Charles Boone at the University of Toronto, and Chad Myers from the University of Minnesota. These groups constructed the first large scale trigenic interaction map of genes that affect colony growth in the yeast S. cerevisiae. The growth of these triple-deletion strains was compared with the growth of the strains harboring single or double deletions in the relevant genes. Given that a total of 36 billion potential trigenic interactions can occur in yeast, this study starts with a set of query strains carrying 302 single gene mutations and 151 double gene mutations. These query strains were tested for genetic interactions versus an array of 1182 strains, each carrying a mutation in an informative gene, so that most general biological processes were included. Thus, in total close to 200,000 trigenic interactions (∼0.0006% of all possible combinations) were tested. Dr. Walhout discusses the implications and future directions from the results of this study.
Walhout AJM (2018). If two deletions don’t stop growth, try three. Science, 360(6386), 269–270.
Kuzmin E, VanderSluis B, Wang W, Tan G, Deshpande R, Chen Y, Usaj M, Balint A, Mattiazzi Usaj M, van Leeuwen J, Koch EN, Pons C, Dagilis AJ, Pryszlak M, Wang JZY, Hanchard J, Riggi M, Xu K, Heydari H, San Luis BJ, Shuteriqi E, Zhu H, Van Dyk N, Sharifpoor S, Costanzo M, Loewith R, Caudy A, Bolnick D, Brown GW, Andrews BJ, Boone C, Myers CL. (2018). Systematic analysis of complex genetic interactions. Science, 360(6386).
Vitamin B12 functions as a cofactor for methionine synthase to produce the anabolic methyl donor S-adenosylmethionine (SAM) and for methylmalonyl-CoA mutase to catabolize the short-chain fatty acid propionate. In the nematode Caenorhabditis elegans, maternally supplied vitamin B12 is required for the development of offspring. However, the mechanism for exporting vitamin B12 from the mother to the offspring is not yet known. Here, we use RNAi of more than 200 transporters with a vitamin B12-sensor transgene to identify the ABC transporter MRP-5 as a candidate vitamin B12 exporter. We show that the injection of vitamin B12 into the gonad of mrp-5 deficient mothers rescues embryonic lethality in the offspring. Altogether, our findings identify a maternal mechanism for the transit of an essential vitamin to support the development of the next generation.
Huimin N, Ponomarova O, Giese GE, Walhout AJM. (2018). C. elegans MRP-5 Exports Vitamin B12 from Mother to Offspring to Support Embryonic Development. Cell Reports 22, 3126-3133.