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FOXO/DAF-16 modulates the transcription factor ROR/NHR-23 and inhibits the let-7 microRNA to maintain multipotency during dauer

ABSTRACT: Animals rapidly reprogram gene expression to adapt development to environmental stress. How gene regulatory programs that drive continuous development are repressed during stress-induced developmental arrest remains poorly understood. In Caenorhabditis elegans, starvation and overcrowding trigger entry into the stress-resistant, quiescent dauer stage. Here, we identify interactions among the conserved transcription factors DAF-16/FOXO and NHR-23/ROR, and the let-7 family of microRNAs as key regulators of the switch from continuous development to dauer. We show that loss of daf-16 during dauer causes elevated let-7 family microRNAs and premature expression of the adult collagen reporter col-19p::GFP. Reducing let-7 family activity suppresses this phenotype, whereas dauer-specific let-7 expression is sufficient to induce col-19p::GFP expression. Mechanistically, DAF-16 inhibits let-7 transcription in part by repressing nhr-23, which encodes a transcriptional activator of the let-7 family and molting-cycle genes. ChIP-seq analysis reveals DAF-16 binding upstream of nhr-23, and daf-16; daf-7 mutant dauers exhibit increased nhr-23 mRNA and NHR-23 protein, supporting a model in which DAF-16 directly represses nhr-23. Integrated ChIP-seq and transcriptomic analyses identify 1,183 genes activated and 681 genes repressed by DAF-16 during dauer. Repressed targets are enriched for pro-growth genes involved in mitotic DNA replication and translational elongation. DAF-16 targets include 59 transcription factors that may mediate broader transcriptional reprogramming during dauer to maintain multipotency and establish quiescence. Together, these findings reveal that DAF-16/FOXO establishes stress-induced developmental arrest by coupling activation of protective pathways with repression of conserved developmental timing, growth, and differentiation programs.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE338292 | GEO | 2026/07/17

REPOSITORIES: GEO

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Project description: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.

Project description:Post-embryonic development of the nematode C. elegans is governed by nutrient availability. L1-stage larvae remain in a state of developmental arrest after hatching until they feed. This “L1 arrest” (or "L1 diapause") is associated with increased stress resistance, supporting starvation survival. Loss of the transcription factor daf-16/FOXO, an effector of insulin/IGF signaling, results in arrest-defective and starvation-sensitive phenotypes. We show that daf-16/FOXO regulates L1 arrest cell-nonautonomously, suggesting that insulin/IGF signaling regulates at least one additional signaling pathway. We used mRNA-seq to identify candidate signaling molecules affected by daf-16/FOXO during L1 arrest. daf-16/FOXO had overlapping but distinct effects on gene expression in L1 arrest compared to daf-2/InsR adults. Notably, dbl-1/TGF-β, a ligand for the Sma/Mab pathway, and daf-36, which encodes an upstream component of the daf-12/NHR steroid hormone signaling pathway, were up-regulated during L1 arrest in a daf-16/FOXO mutant. Using genetic epistasis analysis, we show that dbl-1/TGF-β and daf-12/NHR steroid hormone signaling pathways are required for the daf-16/FOXO arrest-defective phenotype, suggesting that daf-16/FOXO represses dbl-1/TGF-β and daf-36. The dbl-1/TGF-β and daf-12/NHR pathways have not previously been shown to affect L1 development, but we found that disruption of these pathways delayed L1 development in fed larvae, consistent with these pathways promoting development in starved daf-16/FOXO mutants. Though the dbl-1/TGF-β and daf-12/NHR pathways are epistatic to daf-16/FOXO for the arrest-defective phenotype, disruption of these pathways does not suppress starvation sensitivity of daf-16/FOXO mutants. This observation uncouples starvation survival from developmental arrest, indicating that DAF-16/FOXO targets distinct effectors for each phenotype, and revealing that inappropriate development during starvation does not cause the early demise of daf-16/FOXO mutants. Overall, this study shows that daf-16/FOXO promotes developmental arrest cell-nonautonomously by repressing pathways that promote larval development.

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FOXO/DAF-16 modulates the transcription factor ROR/NHR-23 and inhibits the let-7 microRNA to maintain multipotency during dauer

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