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bioRxiv · 10.64898/2026.05.29.728887

Nutrient-responsive and DAF-16/FoxO target H1 histone HIL-1 promotes resistance to starvation and bacterial pathogens in Caenorhabditis elegans

Fisher, K.·Chitrakar, R.·Baugh, L. R.
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Abstract

Insulin/IGF-1 signaling (IIS) mediates metabolic and developmental acclimation to stressful conditions including starvation. The transcription factor DAF-16/FoxO actuates many of the physiological effects of reduced IIS, yet the specific contributions of DAF-16 target genes to stress resistance remain poorly understood. We explore the function of C. elegans H1 linker histone HIL-1/H1.0, a DAF-16 target that is upregulated during starvation. The HIL-1 sequence is divergent from the other eight annotated C. elegans H1 variants, and the others are not so highly responsive to nutrient availability and DAF-16 activity, suggesting distinct function. Using knock-in reporters, we find that HIL-1 is broadly expressed in nuclei of L1 and dauer larvae during starvation, but that expression is largely undetectable in fed larvae. Disrupting hil-1 activity through mutation or auxin-inducible degradation led to reduced growth after extended L1 starvation, revealing reduced starvation resistance. RNA-seq of hil-1 mutants suggested that HIL-1 activates genes involved in the innate immune response, and hil-1 mutants display compromised survival upon exposure to Pseudomonas aeruginosa under reduced IIS. Together these results suggest that DAF-16/FoxO activates transcription of hil-1 during starvation to promote resistance to starvation and pathogens. We demonstrate conditional regulation of an H1 histone, and we reveal a novel mechanism for how IIS promotes stress resistance by identifying a histone variant that connects nutrient sensing to immunity. ARTICLE SUMMARYH1 histones promote condensation of chromatin. Like many other organisms, the roundworm Caenorhabditis elegans has several H1 histones, but their regulation and function is unclear. We were intrigued by hil-1/H1.0 because it is dramatically up-regulated during starvation in daf-16/FoxO-dependent fashion. Insulin/IGF signaling regulates DAF-16, and DAF-16 is critical to starvation resistance. We used genome editing to create alleles to interrogate hil-1 expression and function. We show HIL-1 is expressed throughout the animal during starvation, it activates expression of immunity genes, and it promotes resistance to starvation and a bacterial pathogen. This work demonstrates a connection between nutrient sensing and immunity.

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Fisher, K., Chitrakar, R., Baugh, L. R.. 2026-06-02. Nutrient-responsive and DAF-16/FoxO target H1 histone HIL-1 promotes resistance to starvation and bacterial pathogens in Caenorhabditis elegans. https://doi.org/10.64898/2026.05.29.728887

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