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Histone H3K9 methylation regulates chronic stress and IL‐6–induced colon epithelial permeability and visceral pain
Author(s) -
Wiley John W.,
Zong Ye,
Zheng Gen,
Zhu Shengtao,
Hong Shuangsong
Publication year - 2020
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.13941
Subject(s) - occludin , methylation , endocrinology , medicine , intestinal permeability , chronic stress , cancer research , tight junction , biology , microbiology and biotechnology , biochemistry , gene
Background Chronic stress is associated with activation of the HPA axis, elevation in pro‐inflammatory cytokines, decrease in intestinal epithelial cell tight junction (TJ) proteins, and enhanced visceral pain. It is unknown whether epigenetic regulatory pathways play a role in chronic stress–induced intestinal barrier dysfunction and visceral hyperalgesia. Methods Young adult male rats were subjected to water avoidance stress ± H3K9 methylation inhibitors or siRNAs. Visceral pain response was assessed. Differentiated Caco‐2/BBE cells and human colonoids were treated with cortisol or IL‐6 ± antagonists. Expression of TJ, IL‐6, and H3K9 methylation status at gene promoters was measured. Transepithelial electrical resistance and FITC‐dextran permeability were evaluated. Key Results Chronic stress induced IL‐6 up‐regulation prior to a decrease in TJ proteins in the rat colon. The IL‐6 level inversely correlated with occludin expression. Treatment with IL‐6 decreased occludin and induced visceral hyperalgesia. Chronic stress and IL‐6 increased H3K9 methylation and decreased transcriptional GR binding to the occludin gene promoter, leading to down‐regulation of protein expression and increase in paracellular permeability. Intrarectal administration of a H3K9 methylation antagonist prevented chronic stress–induced visceral hyperalgesia in the rat. In a human colonoid model, cortisol decreased occludin expression, which was prevented by the GR antagonist RU486, and IL‐6 increased H3K9 methylation and decreased TJ protein levels, which were prevented by inhibitors of H3K9 methylation. Conclusions & Inferences Our findings support a novel role for methylation of the repressive histone H3K9 to regulate chronic stress, pro‐inflammatory cytokine–mediated reduction in colon TJ protein levels, and increase in paracellular permeability and visceral hyperalgesia.