Transcriptomic and chromatin accessibility profiling unveils new regulators of heat hormesis in Caenorhabditis elegans

Heat hormesis describes the beneficial adaptations from transient exposure to mild heat stress, which enhances stress resilience and promotes healthy aging. It is thought to be the underlying basis of popular wellness practices like sauna therapy. Despite extensive documentation across species, the molecular basis of the long-term protective effects of heat hormesis remain poorly understood. This study bridges that critical gap through a comprehensive multiomic analysis, providing key insights into the transcriptomic and chromatin accessibility landscapes throughout a heat hormesis regimen adapted in C. elegans. We uncover highly dynamic dose-dependent molecular responses to heat stress and reveal that while most initial stress-induced changes revert to baseline, key differences in response to subsequent heat shock challenge are directly linked to physiological benefits. We identify new regulators of heat hormesis, including MARS-1/MARS1, SNPC-4/SNAPc, ELT-2/GATA4, FOS-1/c-Fos, and DPY-27/SMC4, which likely orchestrate gene expression programs that enhance stress resilience through distinct biological pathways. This study advances our understanding of stress resilience mechanisms, points to multiple new avenues of future investigations, and suggests potential strategies for promoting healthy aging through mid-life stress management.