Glucocorticoid receptor-mediated Nr1d1 chromatin circadian misalignment in stress-induced irritable bowel syndrome

Gen Zheng; Suya Pang; Junbao Wang; Fangyu Wang; Qi Wang; Lili Yang; Mengdie Ji; Dejian Xie; Shengtao Zhu; Yang Chen; Yan Zhou; Gerald A Higgins; John W Wiley; Xiaohua Hou; Rong Lin

doi:10.1016/j.isci.2023.107137

Glucocorticoid receptor-mediated Nr1d1 chromatin circadian misalignment in stress-induced irritable bowel syndrome

iScience. 2023 Jun 17;26(7):107137. doi: 10.1016/j.isci.2023.107137. eCollection 2023 Jul 21.

Authors

Gen Zheng¹, Suya Pang¹, Junbao Wang², Fangyu Wang², Qi Wang³, Lili Yang⁴, Mengdie Ji³, Dejian Xie⁵, Shengtao Zhu⁶, Yang Chen³, Yan Zhou², Gerald A Higgins⁷, John W Wiley⁸, Xiaohua Hou¹, Rong Lin¹

Affiliations

¹ Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
² Medical Research Institute at School of Medicine, Wuhan University, Wuhan 430072, China.
³ 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.
⁴ Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, Kunming Medical University, Kunming 650500, China.
⁵ Beijing Research Center, Wuhan Frasergen Bioinformatics Co., Ltd, Beijing 100081, China.
⁶ Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
⁷ Department of Computational Medicine and Bioinformatics, Medical School, University of Michigan, Ann Arbor 48109, MI, USA.
⁸ Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor 48109, MI, USA.

Abstract

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.

Keywords: Molecular biology; Neuroscience; Transcriptomics.