skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.


Title: Context-specific regulation of lysosomal lipolysis through network-level diverting of transcription factor interactions
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.”  more » « less
Award ID(s):
1715826
PAR ID:
10333724
Author(s) / Creator(s):
; ; ; ; ; ; ;
Date Published:
Journal Name:
Proceedings of the National Academy of Sciences
Volume:
118
Issue:
41
ISSN:
0027-8424
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Murphy, Coleen T. (Ed.)
    Many tissue-specific stem cells maintain the ability to produce multiple cell types during long periods of non-division, or quiescence. FOXO transcription factors promote quiescence and stem cell maintenance, but the mechanisms by which FOXO proteins promote multipotency during quiescence are still emerging. The single FOXO ortholog in C . elegans , daf-16 , promotes entry into a quiescent and stress-resistant larval stage called dauer in response to adverse environmental cues. During dauer, stem and progenitor cells maintain or re-establish multipotency to allow normal development to resume after dauer. We find that during dauer, daf-16 /FOXO prevents epidermal stem cells (seam cells) from prematurely adopting differentiated, adult characteristics. In particular, dauer larvae that lack daf-16 misexpress collagens that are normally adult-enriched. Using col-19p :: gfp as an adult cell fate marker, we find that all major daf-16 isoforms contribute to opposing col-19p :: gfp expression during dauer. By contrast, daf-16(0) larvae that undergo non-dauer development do not misexpress col-19p :: gfp . Adult cell fate and the timing of col-19p :: gfp expression are regulated by the heterochronic gene network, including lin-41 and lin-29 . lin-41 encodes an RNA-binding protein orthologous to LIN41/TRIM71 in mammals, and lin-29 encodes a conserved zinc finger transcription factor. In non-dauer development, lin-41 opposes adult cell fate by inhibiting the translation of lin-29 , which directly activates col-19 transcription and promotes adult cell fate. We find that during dauer, lin-41 blocks col-19p :: gfp expression, but surprisingly, lin-29 is not required in this context. Additionally, daf-16 promotes the expression of lin-41 in dauer larvae. The col-19p :: gfp misexpression phenotype observed in dauer larvae with reduced daf-16 requires the downregulation of lin-41 , but does not require lin-29 . Taken together, this work demonstrates a novel role for daf-16 /FOXO as a heterochronic gene that promotes expression of lin-41/ TRIM71 to contribute to multipotent cell fate in a quiescent stem cell model. 
    more » « less
  2. Ashrafi, Kaveh (Ed.)
    Animals integrate changes in external and internal environments to generate behavior. While neural circuits detecting external cues have been mapped, less is known about how internal states like hunger are integrated into behavioral outputs. Here, we use the nematode C . elegans to examine how changes in internal nutritional status affect chemosensory behaviors. We show that acute food deprivation leads to a reversible decline in repellent, but not attractant, sensitivity. This behavioral change requires two conserved transcription factors MML-1 (MondoA) and HLH-30 (TFEB), both of which translocate from the intestinal nuclei to the cytoplasm during food deprivation. Next, we identify the insulin-like peptide INS-31 as a candidate ligand relaying food-status signals from the intestine to other tissues. Further, we show that neurons likely use the DAF-2 insulin receptor and AGE-1/PI-3 Kinase, but not DAF-16/FOXO to integrate these intestine-released peptides. Altogether, our study shows how internal food status signals are integrated by transcription factors and intestine-neuron signaling to generate flexible behaviors via the gut-brain axis. 
    more » « less
  3. FOXO transcription factors regulate development, longevity, and stress-resistance across species. The C. elegans FOXO ortholog, daf-16, has three major isoforms with distinct promoters and N-termini. Different combinations of isoforms regulate different processes. Adverse environments can induce dauer diapause after the second larval molt. During dauer, daf-16 blocks specification of vulval precursor cells, including EGFR/Ras-mediated 1˚ fate specification and LIN-12/Notch-mediated 2˚ fate specification. Using isoform-specific mutants, we find that daf-16a and daf-16f are functionally redundant for the block to the expression of 1˚ fate markers. In contrast, all three isoforms contribute to blocking the expression of 2˚ fate markers. 
    more » « less
  4. Abstract Mitochondrial stress within the nervous system can trigger non-cell autonomous responses in peripheral tissues. However, the specific neurons involved and their impact on organismal aging and health have remained incompletely understood. Here, we demonstrate that mitochondrial stress in γ-aminobutyric acid-producing (GABAergic) neurons inCaenorhabditis elegans(C. elegans) is sufficient to significantly alter organismal lifespan, stress tolerance, and reproductive capabilities. This mitochondrial stress also leads to significant changes in mitochondrial mass, energy production, and levels of reactive oxygen species (ROS). DAF-16/FoxO activity is enhanced by GABAergic neuronal mitochondrial stress and mediates the induction of these non-cell-autonomous effects. Moreover, our findings indicate that GABA signaling operates within the same pathway as mitochondrial stress in GABAergic neurons, resulting in non-cell-autonomous alterations in organismal stress tolerance and longevity. In summary, these data suggest the crucial role of GABAergic neurons in detecting mitochondrial stress and orchestrating non-cell-autonomous changes throughout the organism. 
    more » « less
  5. Kicheva, Anna Kostadinova (Ed.)
    Individual signaling pathways, such as fibroblast growth factors (FGFs), can regulate a plethora of inductive events. According to current paradigms, signal-dependent transcription factors (TFs), such as FGF/MapK-activated Ets family factors, partner with lineage-determining factors to achieve regulatory specificity. However, many aspects of this model have not been rigorously investigated. One key question relates to whether lineage-determining factors dictate lineage-specific responses to inductive signals or facilitate these responses in collaboration with other inputs. We utilize the chordate modelCiona robustato investigate mechanisms generating lineage-specific induction. Previous studies inC.robustahave shown that cardiopharyngeal progenitor cells are specified through the combined activity of FGF-activatedEts1/2.band an inferred ATTA-binding transcriptional cofactor. Here, we show that the homeobox TFLhx3/4serves as the lineage-determining TF that dictates cardiopharyngeal-specific transcription in response to pleiotropic FGF signaling. Targeted knockdown ofLhx3/4leads to loss of cardiopharyngeal gene expression. Strikingly, ectopic expression ofLhx3/4in a neuroectodermal lineage subject to FGF-dependent specification leads to ectopic cardiopharyngeal gene expression in this lineage. Furthermore, ectopicLhx3/4expression disrupts neural plate morphogenesis, generating aberrant cell behaviors associated with execution of incompatible morphogenetic programs. Based on these findings, we propose that combinatorial regulation by signal-dependent and lineage-determinant factors represents a generalizable, previously uncategorized regulatory subcircuit we term “cofactor-dependent induction.” Integration of this subcircuit into theoretical models will facilitate accurate predictions regarding the impact of gene regulatory network rewiring on evolutionary diversification and disease ontogeny. 
    more » « less