Every cell must coordinate and regulate thousands of genes in a robust manner to ensure cellular function. Complex gene regulation is needed for most biological processes, such as development, physiological homeostasis, and response to environmental stresses. Networks of genes have evolved to coordinate and integrate biological processes within a cell and subsequently regulate the fate of the organism.
The Walhout lab wishes to understand gene regulatory networks and how these networks adapt to different conditions. We use systems biology approaches to dissect these complex and robust networks. These approaches combine high-quality and large-scale genetic and biochemical data sets and uses computational modeling to integrate the data such that the organizing principles and emergent properties of biological systems are unveiled.
To examine gene regulatory networks we mainly use the model organism round worm Caenorhabditis elegans. Worms are highly adaptable, easy to manipulate, and have many analogs in human genetics. Furthermore, there are many genetic tools and worm-specific techniques that are not available for studying higher eukaryotes. Overall, our research involves two broad areas of biology…read more…
Click to enlarge. TF–cofactor protein–protein interaction network from Reece‐Hoyes et al (2013) for predicted activators and repressors. Blue, predicted repressors; red, predicted activators; yellow, cofactors; blue outline, co‐repressors; red outline, co‐activators.
Transcription factors (TFs) play a central role in controlling spatiotemporal gene expression and the response to environmental cues. A comprehensive understanding of gene regulation requires integrating physical protein–DNA interactions (PDIs) with TF regulatory activity, expression patterns, and phenotypic data. Although great progress has been made in mapping PDIs using chromatin immunoprecipitation, these studies have only characterized ~10% of TFs in any metazoan species. The nematode C. elegans has been widely used to study gene regulation due to its compact genome with short regulatory sequences. Here, we delineated the largest gene‐centered metazoan PDI network to date by examining interactions between 90% of C. elegans TFs and 15% of gene promoters. We used this network as a backbone to predict TF binding sites for 77 TFs, two‐thirds of which are novel, as well as integrate gene expression, protein–protein interaction, and phenotypic data to predict regulatory and biological functions for multiple genes and TFs.
Fuxman Bass, JI, Pons, C, Kozlowski, L, Reece‐Hoyes, JS, Shrestha, S, Holdorf, AD, Mori, A, Myers, CL, Walhout, AJM. (2016). A gene‐centered C. elegans protein–DNA interaction network provides a framework for functional predictions. Mol. Sys. Biol. 12: 884. doi: 10.15252/msb.20167131
Best wishes to Dr. Juan Fuxman Bass who has left the lab to start his own lab as an Assistant Professor in the Department of Biology at Boston University. He will be working on transcription factors that regulate the immune response. We will miss you Juan!
Dr. Fuxman Bass’s website: https://www.bu.edu/biology/people/profiles/juan-fuxman-bass/
The Walhout lab participated in the annual joint Cancer Center for Systems Biology (CCSB) and Program in Systems Biology (PSB) retreat in Gloucester, MA, on September 7-9. The retreat attendees heard talks from their colleagues in CCSB and PSB, as well as lectures form other invited speakers. Distinguished Professor John Roth of UC Davis opened the retreat with a historical perspective of his work on mutation selection in bacteria. University of Toronto Professor and Howard Hughes Medical Institute Senior International Research Scholar Charlie Boone presented the keynote lecture on genetic networks in yeast, and Tufts University Professor and Howard Hughes Medical Institute Professor David Walt discussed how basic science research lead to the co-founding of the company Illumina. Walhout lab post-doctoral fellows Jingyan Zhang and Huimin Na, and graduate student Aurian Garcia-Gonzalez all gave short talks about their exciting research on C. elegans networks.
Metabolic network rewiring is the rerouting of metabolism through the use of alternate enzymes to adjust pathway flux and accomplish specific anabolic or catabolic objectives. Here, we report the first characterization of two parallel pathways for the breakdown of the short chain fatty acid propionate in Caenorhabditis elegans. Using genetic interaction mapping, gene co-expression analysis, pathway intermediate quantification and carbon tracing, we uncover a vitamin B12-independent propionate breakdown shunt that is transcriptionally activated on vitamin B12 deficient diets, or under genetic conditions mimicking the human diseases propionic- and methylmalonic acidemia, in which the canonical B12-dependent propionate breakdown pathway is blocked. Our study presents the first example of transcriptional vitamin-directed metabolic network rewiring to promote survival under vitamin deficiency. The ability to reroute propionate breakdown according to B12 availability may provide C. elegans with metabolic plasticity and thus a selective advantage on different diets in the wild.
Watson E, Olin-Sandoval V, Hoy MJ, Li C, Louisse T, Yao V, Mori A, Holdorf AD, Troyanskaya OG, Ralser M, Walhout AJM (2016) Metabolic network rewiring of propionate flux compensates vitamin B12 deficiency in C. elegans. eLife, doi: 10.7554/eLife.17670