Histone H3K9 methylation regulates chronic stress and IL-6–induced colon epithelial permeability and visceral pain
John W. Wiley
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
Search for more papers by this authorYe Zong
Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorGen Zheng
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
Search for more papers by this authorShengtao Zhu
Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorCorresponding Author
Shuangsong Hong
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
Correspondence
Shuangsong Hong, Department of Internal Medicine, University of Michigan, 1150 W Medical Center Dr., Room 9315, MSRB III, Ann Arbor, MI 48109, USA.
Email: [email protected]
Search for more papers by this authorJohn W. Wiley
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
Search for more papers by this authorYe Zong
Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorGen Zheng
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
Search for more papers by this authorShengtao Zhu
Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorCorresponding Author
Shuangsong Hong
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
Correspondence
Shuangsong Hong, Department of Internal Medicine, University of Michigan, 1150 W Medical Center Dr., Room 9315, MSRB III, Ann Arbor, MI 48109, USA.
Email: [email protected]
Search for more papers by this authorFunding information
This study was supported by NIH R01DK098205 (JWW), NIH R21AT009253 (JWW/SH), and NIH R21NS113127 (JWW/SH), and by Pilot/Feasibility grant to SH from the University of Michigan Center for Gastrointestinal Research (NIH grant P30 DK34933).
Abstract
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.
CONFLICT OF INTEREST
The authors have declared that no conflict of interest exists.
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