Context-specific regulation of lysosomal lipolysis through network-level diverting of transcription factor interactions

Abstract

Plasticity in multicellular organisms involves signaling pathways converting contexts-either natural environmental challenges or laboratory perturbations-into context-specific changes in gene expression. Congruently, the interactions between the signaling molecules and transcription factors (TF) 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. Reconciling these stable TF-target gene pair inferences with the context-specific nature of homeostatic responses is therefore needed. The induction of the <i>Caenorhabditis elegans</i> genes <i>lipl-3</i> and <i>lipl-4</i> is observed in many genetic contexts and is essential to survival during fasting. We find DAF-16/FOXO mediating <i>lipl-4</i> induction in all contexts tested; hence, <i>lipl-4</i> regulation seems context independent and compatible with across-context inferences. In contrast, DAF-16-mediated regulation of <i>lipl-3</i> is context specific. DAF-16 reduces the induction of <i>lipl-3</i> during fasting, yet it promotes it during oxidative stress. Through discrete dynamic modeling and genetic epistasis, we define that DAF-16 represses HLH-30/TFEB-the main TF activating <i>lipl-3</i> during fasting. Contrastingly, DAF-16 activates the stress-responsive TF HSF-1 during oxidative stress, which promotes <i>C. elegans</i> survival through induction of <i>lipl-3</i> Furthermore, 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 how context-specific diverting of functional interactions within a molecular network allows cells to specifically respond to a large number of contexts with a limited number of molecular players, a mode of transcriptional regulation we name "contextualized transcription."