RRC ID 76016
Author Mony VK, Drangowska-Way A, Albert R, Harrison E, Ghaddar A, Horak MK, Ke W, O'Rourke EJ.
Title Context-specific regulation of lysosomal lipolysis through network-level diverting of transcription factor interactions.
Journal Proc Natl Acad Sci U S A
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 Caenorhabditis elegans genes lipl-3 and lipl-4 is observed in many genetic contexts and is essential to survival during fasting. 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. In contrast, DAF-16-mediated regulation of lipl-3 is context specific. DAF-16 reduces the induction of lipl-3 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 lipl-3 during fasting. Contrastingly, DAF-16 activates the stress-responsive TF HSF-1 during oxidative stress, which promotes C. elegans survival through induction of lipl-3 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."
Volume 118(41)
Published 2021-10-12
DOI 10.1073/pnas.2104832118
PII 2104832118
PMID 34607947
PMC PMC8521664
MeSH Animals Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors Basic Helix-Loop-Helix Transcription Factors / metabolism Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / antagonists & inhibitors Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Carboxylic Ester Hydrolases / antagonists & inhibitors Carboxylic Ester Hydrolases / genetics Carboxylic Ester Hydrolases / metabolism Fasting / physiology* Forkhead Transcription Factors / metabolism* Gene Expression Regulation / genetics* Lipase / genetics Lipase / metabolism* Lipolysis / physiology Oxidative Stress / physiology* Signal Transduction / physiology Transcription Factors / metabolism Transcription, Genetic / genetics Transcriptional Activation / physiology
C.elegans tm1978 tm2182 tm1011 tm4063