Abstract
Plasticity in multicellular organisms involves signaling pathways converting contexts into context-specific changes in gene expression. Contexts range from environmental changes such as seasonal or daily dietary changes to changes in the microbiome composition or the acute effect of stressors (chemical, physical or biological). Context can also refer to penetrant loss or gain of function mutations. In the lab, contexts include distinct mutant backgrounds, culture media, microbiomes, cells, and tissue types, among others. Studies have shown that context can change the phenotypic outcome of a perturbation. Congruently, the signaling molecule-transcription factor (TF) interactions regulating these responses are also context-specific. However, when a target gene responds across contexts, the upstream TF identified in one context is often inferred to regulate it across contexts. Hence, reconciling these stable TF-target gene pair inferences with the context-specific nature of homeostatic responses is needed. The induction of the C. elegans genes lipl-1, lipl-3, and lipl-4 is essential to survival during fasting and is observed in many genetic contexts. We find DAF-16/FOXO mediating lipl-4 induction in all contexts tested; hence, lipl-4 regulation seems context-independent and compatible with across-context inferences. Contrastingly, DAF-16 activates the stress-responsive TF HSF-1 during oxidative stress, promoting C. elegans survival through induction of lipl-3. Further, the TF MXL-3 contributes to the dominance of HSF-1 at the expense of HLH-30 during oxidative stress but not during fasting. This study shows the limitations of across-context inferences and how context-specific diverting of interactions within a network allows cells to specifically respond to many contexts with a limited number of molecular players. In summary, context is a critical variable in gene regulation, particularly for genes promiscuously activated or repressed across multiple stresses or physiological responses. Inferring the gene regulatory pathways based on studies carried out in different contexts played an essential role in creating the current body of knowledge. However, as we aim to understand more deeply the gene regulatory pathways acting in health and disease, we need to acknowledge that inferences can be misleading and even hinder discovery.
