Andrew Capaldi and Erin O’Shea
The gene expression program in a cell is set in response to the level, timing and combination of hundreds of developmental and environmental stimuli. This precise control depends on a network of signaling pathways, transcription factors (TFs) and gene promoters that work together to not only process the information a cell receives but to create the appropriate output as well. But what do these networks look like and how do they work?
To address these questions we developed a new approach to dissecting transcriptional networks where we analyze the global gene expression profile of a set of strains, each of which has a different combination of signaling proteins and/or TFs deleted, using DNA microarrays. Putting these array data together we are then able to build a quantitative circuit diagram that describe how signals combine to influence TF activity and how these TFs cooperate to regulate each and every gene in the genome. In addition, we can identify points (nodes) in the network that are activated or repressed by unknown factors. Applying our approach to understand the osmotic (salt) stress response in budding yeast we discovered that the pathway responsible for responding to changes in osmolarity cooperates with a general stress response pathway both at the level of TF activation and at the level of promoter binding, to integrate information. This network structure suggested to us that the osmotic stress response activated in yeast is tuned both at a global level, and at a gene specific level, by the general stress pathway; a conclusion we went on to confirm. We expect that other transcriptional networks will have a similar structure in order to create a context dependent response. Moving forward we hope to apply our new method to other signaling systems to understand transcriptional network function in both health and disease.
Read more in Nature Genetics