Li Hailong, Li Jinhe, Xiao Ting, Hu Yayue, Yang Ying, Gu Xiaoting, Jin Ge, Cao Hailong, Zhou Honggang, Yang Cheng
The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin, China.
Front Pharmacol. 2022 Jul 14;13:904420. doi: 10.3389/fphar.2022.904420. eCollection 2022.
The super-enhancer, a cluster of enhancers with strong transcriptional activity, has become one of the most interesting topics in recent years. This study aimed to investigate pathogenic super-enhancer-driven genes in IBD and screen therapeutic drugs based on the results. In this study, through the analysis of differentially expressed genes in colitis patients from the GEO database and the analysis of the super-enhancer-associated database, we found that the super-enhancer pathogenic genes PCK1 and EFNA1 were simultaneously regulated by transcription factor CEBPB through two super-enhancers (sc-CHR20-57528535 and sc-CHR1-155093980). Silencing CEBPB could significantly inhibit the expression of PCK1 and EFNA1 and enhance the expression of epithelial barrier proteins claudin-1, occludin, and ZO-1. In LPS-induced Caco-2 cells, drugs commonly used in clinical colitis including tofacitinib, oxalazine, mesalazine, and sulfasalazine inhibited mRNA levels of CEBPB, PCK1, and EFNA1. In the drug screening, we found that nintedanib significantly inhibited the mRNA and protein levels of CEBPB, PCK1, and EFNA1. experiments, nintedanib significantly alleviated DSS-induced colitis in mice by inhibiting CEBPB/PCK1 and CEBPB/EFNA1 signaling pathways. At the genus level, nintedanib improved the composition of the gut microbiota in mice with DSS-induced experimental colitis. In conclusion, we found that PCK1 and EFNA1 are highly expressed in colitis and they are regulated by CEBPB through two super-enhancers, and we further demonstrate their role and . Nintedanib may be a potential treatment for IBD. Super-enhancers may be a new way to explore the pathogenesis of colitis.
超级增强子是一类具有强大转录活性的增强子簇，近年来已成为最受关注的话题之一。本研究旨在探究炎症性肠病中由致病性超级增强子驱动的基因，并根据研究结果筛选治疗药物。在本研究中，通过对来自基因表达综合数据库（GEO数据库）的结肠炎患者差异表达基因进行分析以及对超级增强子相关数据库进行分析，我们发现超级增强子致病基因磷酸烯醇式丙酮酸羧激酶1（PCK1）和 Ephrin A1（EFNA1）通过两个超级增强子（sc-CHR20-57528535 和 sc-CHR1-155093980）同时受转录因子CCAAT/增强子结合蛋白β（CEBPB）调控。沉默CEBPB可显著抑制PCK1和EFNA1的表达，并增强上皮屏障蛋白闭合蛋白1（claudin-1）、闭锁蛋白（occludin）和紧密连接蛋白1（ZO-1）的表达。在脂多糖（LPS）诱导的人结肠腺癌细胞（Caco-2细胞）中，临床治疗结肠炎常用的药物，包括托法替布、奥沙拉嗪、美沙拉嗪和柳氮磺胺吡啶，均可抑制CEBPB、PCK1和EFNA1的mRNA水平。在药物筛选过程中，我们发现尼达尼布可显著抑制CEBPB、PCK1和EFNA1的mRNA及蛋白水平。实验表明，尼达尼布通过抑制CEBPB/PCK1和CEBPB/EFNA1信号通路，显著减轻了葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎。在属水平上，尼达尼布改善了DSS诱导的实验性结肠炎小鼠的肠道微生物群组成。总之，我们发现PCK1和EFNA1在结肠炎中高表达，且它们受CEBPB通过两个超级增强子调控，我们进一步证实了它们的作用，并且发现尼达尼布可能是炎症性肠病的一种潜在治疗药物。超级增强子可能是探索结肠炎发病机制的一种新途径。
