Detection of Synergistic Combinatorial Perturbations by a Bifurcation-Based Approach

Drug combination has become an attractive strategy against complex diseases, despite the challenges in handling a large number of possible combinations among candidate drugs. How to detect effective drug combinations and determine the dosage of each drug in the combination is still a challenging task. When regarding a drug as a perturbation, we propose a bifurcation-based approach to detect synergistic combinatorial perturbations. In the approach, parameters of a dynamical system are divided into two groups according to their responses to perturbations. By combining two parameters chosen from two groups, three types of combinations can be obtained. Synergism for different perturbation combinations can be detected by relative positions of the bifurcation curve and the isobole. The bifurcation-based approach can be used not only to detect combinatorial perturbations but also to determine their perturbation quantities. To demonstrate the effectiveness of the approach, we apply it to the epithelial-to-mesenchymal transition (EMT) network. The approach has implications for the rational design of drug combinations and other combinatorial control, e.g. combinatorial regulation of gene expression.

An olfactory pattern generator for on-demand combinatorial control of receptor activities

Olfactory systems employ combinatorial receptor codes for odors. Systematically generating stimuli that address the combinatorial possibilities of an olfactory code poses unique challenges. Here, we present a stimulus method to probe the combinatorial code, demonstrated using the Drosophila larva. This method leverages a set of primary odorants, each of which targets the activity of one olfactory receptor neuron (ORN) type at an optimal concentration. Our setup uses microfluidics to mix any combination of primary odorants on demand to activate any desired combination of ORNs. We use this olfactory pattern generator to demonstrate a spatially distributed olfactory representation in the dendrites of a single interneuron in the antennal lobe, the first olfactory neuropil of the larva. In the larval mushroom body, the next processing layer, we characterize diverse receptive fields of a population of Kenyon cells. The precision and flexibility of the olfactory pattern generator will facilitate systematic studies of processing and transformation of the olfactory code.

Decoupling transcription factor expression and activity enables dimmer switch gene regulation

Gene-regulatory networks achieve complex mappings of inputs to outputs through mechanisms that are poorly understood. We found that in the galactose-responsive pathway in Saccharomyces cerevisiae, the decision to activate the transcription of genes encoding pathway components is controlled independently from the expression level, resulting in behavior resembling that of a mechanical dimmer switch. This was not a direct result of chromatin regulation or combinatorial control at galactose-responsive promoters; rather, this behavior was achieved by hierarchical regulation of the expression and activity of a single transcription factor. Hierarchical regulation is ubiquitous, and thus dimmer switch regulation is likely a key feature of many biological systems. Dimmer switch gene regulation may allow cells to fine-tune their responses to multi-input environments on both physiological and evolutionary time scales.

Combinatorial Control of Plant Specialized Metabolism: Mechanisms, Functions, and Consequences

Plants constantly perceive internal and external cues, many of which they need to address to safeguard their proper development and survival. They respond to these cues by selective activation of specific metabolic pathways involving a plethora of molecular players that act and interact in complex networks. In this review, we illustrate and discuss the complexity in the combinatorial control of plant specialized metabolism. We hereby go beyond the intuitive concept of combinatorial control as exerted by modular-acting complexes of transcription factors that govern expression of specialized metabolism genes. To extend this discussion, we also consider all known hierarchical levels of regulation of plant specialized metabolism and their interfaces by referring to reported regulatory concepts from the plant field. Finally, we speculate on possible yet-to-be-discovered regulatory principles of plant specialized metabolism that are inspired by knowledge from other kingdoms of life and areas of biological research.

Decoupling transcription factor expression and activity enables dimmer-switch gene regulation

Our mechanistic understanding of how gene regulatory networks can achieve complex biological responses is limited. We find that the galactose-responsive pathway in S. cerevisiae has a complex behavior - the decision to induce is controlled independently from the induction level, resembling a mechanical dimmer-switch. Surprisingly, this behavior is not achieved directly through chromatin regulation or combinatorial control at galactose-responsive promoters. Instead, this behavior is achieved by hierarchical regulation of the expression and catalytic activity of a single transcription factor. This genetic motif allows evolution to independently act on both properties, providing a means to tune both resource allocation strategies in dynamic multi-input environments on both physiological and evolutionary time-scales. Hierarchical regulation is ubiquitous and thus dimmer-switch regulation is likely a key feature of many biological systems.