Molecular hydrogen induces beneficial therapeutic effects through epigenetic mechanisms, specifically by modulating histone H3K27 methylation status and activating the mitochondrial unfolded protein response (mtUPR). This study demonstrates that H2 directly regulates gene expression through histone modifications and signaling pathway alterations, suggesting a novel mechanism for its therapeutic efficacy in treating various systemic pathological conditions beyond simple antioxidant effects.
Plain-Language Summary
Researchers gave molecular hydrogen (H2) to rats and mice and studied how it affected gene activity in their livers and lungs. They found that H2 changed the chemical tags on DNA that control which genes turn on or off—specifically affecting a process called histone modification. H2 also activated a cellular stress-response system in mitochondria (the energy-producing parts of cells). This suggests H2 may work through direct changes to how genes are expressed, rather than just acting as an antioxidant.
Abstract
Molecular hydrogen (H2) is a biologically active gas that is used medically to ameliorate various systemic pathological conditions. H2 also regulates gene expression involved in intracellular signaling and metabolic pathways. However, it is unclear whether H2 affects gene expression directly or through indirect effects as a consequence of health improvement. Therefore, we attempted to identify genes that exhibit similar changes in expression in response to H2 by employing DNA microarrays and gene set enrichment analysis to analyze RNA from liver and lung of rats and mice with or without dietary stress. We found that H2 activated the expression of sets of genes regulated by histone H3K27 methylation status. H2 also modified the expression of many genes regulated by a wide variety of signaling pathways. RT-qPCR showed that H2 up-regulated expression of Kcnc3, a H3K27-regulated gene, in organs such as liver, lung, kidney and brain. Furthermore, using immunohistochemistry and immunoblot analysis, we observed changes in H3K27 methylation status in the liver of mice and rats administered H2. Moreover, we showed that H2 simultaneously induced the H3K27 demethylase, Jmjd3, and mitochondrial unfolded protein response (mtUPR)-related genes. Recently, alteration of mitochondrial function was shown to cause induction of H3K27 demethylase or chromatin restructuring, followed by mtUPR activation through the alteration of H3K27 or H3K9 methylation states. Taken together, our study suggests that H2 can induce beneficial effects through mtUPR activation via epigenetic histone modification and by modification of gene expression.
