Zheng Gen, Pang Suya, Wang Junbao, Wang Fangyu, Wang Qi, Yang Lili, Ji Mengdie, Xie Dejian, Zhu Shengtao, Chen Yang, Zhou Yan, Higgins Gerald A, Wiley John W, Hou Xiaohua, Lin Rong
Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Medical Research Institute at School of Medicine, Wuhan University, Wuhan 430072, China.
iScience. 2023 Jun 17;26(7):107137. doi: 10.1016/j.isci.2023.107137. eCollection 2023 Jul 21.
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 in water avoidance stressed (WAS) BALB/c colon epithelium, like in IBS patients. WAS decreased GR binding at the promoter E-box (enhancer box), and GR could suppress via this site. Stress also altered GR binding at the E-box sites along the - chromatin and remodeled circadian chromatin 3D structures, including - super-enhancer, , and . Intestinal deletion of specifically abolished these stress-induced transcriptional alternations relevant to IBS phenotypes in BALB/c mice. GR mediated - chromatin disease related circadian misalignment in stress-induced IBS animal model. This animal model dataset suggests that regulatory SNPs of human - transcription through conserved chromatin looping have translational potential based on the GR-mediated circadian-stress crosstalk.
应激诱导的糖皮质激素升高会导致昼夜节律紊乱和肠脑轴（GBA）失调，包括肠易激综合征（IBS）。我们推测糖皮质激素受体（GR/NR3C1）可能导致结肠上皮细胞中的染色质昼夜节律失调。我们观察到，与IBS患者一样，在避水应激（WAS）的BALB/c小鼠结肠上皮细胞中，核心昼夜节律基因显著减少。WAS降低了GR在启动子E盒（增强子盒）处的结合，并且GR可以通过该位点抑制。应激还改变了GR在沿-染色质的E盒位点处的结合，并重塑了昼夜节律染色质的3D结构，包括-超级增强子、、和。在BALB/c小鼠中，肠道特异性缺失可特异性消除这些与IBS表型相关的应激诱导的转录变化。在应激诱导的IBS动物模型中，GR介导了与-染色质疾病相关的昼夜节律失调。该动物模型数据集表明，基于GR介导的昼夜节律-应激串扰，人类-转录的调控单核苷酸多态性通过保守的染色质环化具有转化潜力。
