We use C. elegans as a model organism to investigate the interplay between chromatin dynamics, gene expression regulation, stress response, and aging. In a recent study, we demonstrated that the highly conserved proteins SET-26/KMT2E and HCF-1 function in the soma to modulate stress response and longevity. Our findings revealed that SET-26 binds to chromatin by recognizing the histone mark H3K4me3, subsequently recruiting HCF-1. Additionally, we identified the histone deacetylase HDA-1 as an antagonist of the SET-26/HCF-1 complex. Interestingly, HDA-1 localizes to genomic regions closely aligned with SET-26 and HCF-1 binding sites but is recruited to chromatin independently of these proteins. Gene expression profiling further demonstrated that SET-26/HCF-1 and HDA-1 exert opposing effects on the expression of specific target genes, likely contributing to their antagonistic roles in longevity. In a parallel study, we explored how chromatin dynamics and gene expression changes mediate the beneficial effects of hormesis. Hormesis, a phenomenon in which prior exposure to mild stress enhances resilience to subsequent stress challenges, has been widely observed across species. We established a robust experimental regimen in which C. elegans primed by mild heat stress exhibited increased resilience to a subsequent lethal heat shock challenge. Chromatin accessibility and transcriptome analyses revealed that both mild heat stress priming and subsequent heat shock induced significant alterations in chromatin accessibility and RNA expression. Notably, the molecular changes induced by priming were largely distinct from those triggered by heat shock alone, suggesting that different levels of heat stress elicit distinct cellular responses. These genomic studies, combined with functional analyses, led to the identification of several novel mediators of the protective effects of hormesis.