Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Suya Pang
Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Junbao Wang
Medical Research Institute at School of Medicine, Wuhan University, Wuhan 430072, China
Fangyu Wang
Medical Research Institute at School of Medicine, Wuhan University, Wuhan 430072, China
Qi Wang
The State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
Lili Yang
Central Laboratory of Yan’an Hospital Affiliated to Kunming Medical University, Kunming Medical University, Kunming 650500, China
Mengdie Ji
The State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
Dejian Xie
Beijing Research Center, Wuhan Frasergen Bioinformatics Co., Ltd, Beijing 100081, China
Shengtao Zhu
Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
Yang Chen
The State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
Yan Zhou
Medical Research Institute at School of Medicine, Wuhan University, Wuhan 430072, China
Gerald A. Higgins
Department of Computational Medicine and Bioinformatics, Medical School, University of Michigan, Ann Arbor 48109, MI, USA
John W. Wiley
Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor 48109, MI, USA
Xiaohua Hou
Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Rong Lin
Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Corresponding author
Summary: Stress-elevated glucocorticoids cause circadian disturbances and gut-brain axis (GBA) disorders, including irritable bowel syndrome (IBS). We hypothesized that the glucocorticoid receptor (GR/NR3C1) might cause chromatin circadian misalignment in the colon epithelium. We observed significantly decreased core circadian gene Nr1d1 in water avoidance stressed (WAS) BALB/c colon epithelium, like in IBS patients. WAS decreased GR binding at the Nr1d1 promoter E-box (enhancer box), and GR could suppress Nr1d1 via this site. Stress also altered GR binding at the E-box sites along the Ikzf3-Nr1d1 chromatin and remodeled circadian chromatin 3D structures, including Ikzf3-Nr1d1 super-enhancer, Dbp, and Npas2. Intestinal deletion of Nr3c1 specifically abolished these stress-induced transcriptional alternations relevant to IBS phenotypes in BALB/c mice. GR mediated Ikzf3-Nr1d1 chromatin disease related circadian misalignment in stress-induced IBS animal model. This animal model dataset suggests that regulatory SNPs of human IKZF3-NR1D1 transcription through conserved chromatin looping have translational potential based on the GR-mediated circadian-stress crosstalk.
