Histone H3.3 chaperone HIRA renders stress‐responsive genes poised for prospective lethal stresses in acquired tolerance

• Published in: Genes to cells : devoted to molecular & cellular mechanisms Vol. 29; no. 9; pp. 722 - 734
• Main Authors: Nagagaki, Yoshikazu, Kozakura, Yuji, Mahandaran, Theventhiran, Fumoto, Yukiko, Nakato, Ryuichiro, Shirahige, Katsuhiko, Ishikawa, Fuyuki
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.09.2024; John Wiley and Sons Inc
• Subjects: Acetylation; acquired tolerance; Chromatin; Chromatin remodeling; Diploids; heat shock protein; Heat stress; HIRA; histone chaperone; Histone H3; histone H3.3; Histones; Hormesis; Hsp70 protein; Methylation; Original; stress response; Temperature effects; HIRA; stress response; heat shock protein; histone H3.3; acquired tolerance; hormesis; histone chaperone; Chromatin remodeling
• ISSN: 1356-9597; 1365-2443; 1365-2443
• DOI: 10.1111/gtc.13140

Appropriate responses to environmental challenges are imperative for the survival of all living organisms. Exposure to low‐dose stresses is recognized to yield increased cellular fitness, a phenomenon termed hormesis. However, our molecular understanding of how cells respond to low‐dose stress remains profoundly limited. Here we report that histone variant H3.3‐specific chaperone, HIRA, is required for acquired tolerance, where low‐dose heat stress exposure confers resistance to subsequent lethal heat stress. We found that human HIRA activates stress‐responsive genes, including HSP70, by depositing histone H3.3 following low‐dose stresses. These genes are also marked with histone H3 Lys‐4 trimethylation and H3 Lys‐9 acetylation, both active chromatin markers. Moreover, depletion of HIRA greatly diminished acquired tolerance, both in normal diploid fibroblasts and in HeLa cells. Collectively, our study revealed that HIRA is required for eliciting adaptive stress responses under environmental fluctuations and is a master regulator of stress tolerance. All living organisms experience ever‐fluctuating environments in the wildlife. We know little about how cells molecularly respond to sublethal mild stresses. In this study, we have demonstrated that mild heat stress render stress‐responsive genes poised for prospective severe heat stress in a histone H3.3 chaperone HIRA‐dependent manner (acquired tolerance, a form of hormesis).