Long noncoding RNA Gm31629 protects against mucosal damage in experimental colitis via YB-1/E2F pathway

Xu Feng,Xiao-Wei Liu,Hai-Yan Zhou,Qi Guo,Tian Su,Chang-Jun Li,Yan Huang,Jun Yi,Mi Yang,Xiang-Hang Luo,Ye Xiao,Jian He

doi:10.1172/jci.insight.150091

Abstract

Mucosal healing is a key treatment goal for inflammatory bowel disease, and adequate epithelial regeneration is required for an intact gut epithelium. However, the underlying mechanism for mucosal healing is unclear. Long noncoding RNAs (lncRNAs) have been reported to be involved in the development of inflammatory bowel disease. Here, we report that a lncRNA named Gm31629 decreased in intestinal epithelial cells in response to inflammatory stimulation. Gm31629 deficiency led to exacerbated intestinal inflammation and delayed epithelial regeneration in dextran sulfate sodium–induced (DSS-induced) colitis model. Mechanistically, Gm31629 promoted E2F pathways and cell proliferation by stabilizing Y-box protein 1 (YB-1), thus facilitating epithelial regeneration. Genetic overexpression of Gm31629 protected against DSS-induced colitis in vivo. Theaflavin 3-gallate, a natural compound mimicking Gm31629, alleviated DSS-induced epithelial inflammation and mucosal damage. These results demonstrate an essential role of lncRNA Gm31629 in linking intestinal inflammation and epithelial cell proliferation, providing a potential therapeutic approach to inflammatory bowel disease.

Highlights

Ulcerative colitis is a form of inflammatory bowel disease characterized by relapsing and remitting diarrhea and bloody stools[1, 2]
RNA fluorescence in situ hybridization validated the constitutive expression of Gm31629 in intestinal epithelial cells, including intestinal stem cells residing at the base of the crypt
dextran sulfate sodium (DSS)-treated mice scored high disease activity index (DAI): continuous body weight loss, progressive diarrhea, and bloody stools, which were absent in mice treated with tap-water (Supplementary Figure 2, A and B)

Summary

Introduction

Ulcerative colitis is a form of inflammatory bowel disease characterized by relapsing and remitting diarrhea and bloody stools[1, 2]. Impaired intestinal epithelial barrier and restricted mucosal inflammation ranging from rectum to proximal colon characterized the common feature of ulcerative colitis pathology[2, 3]. The development of ulcerative colitis is initially driven by intestinal epithelial dysfunction, including increased apoptotic epithelial cells and disrupted tight junctions, which leads to epithelial barrier defect and resultant lamina propria inflammation[3,4,5]. Emerging evidence has proved that dysregulated lncRNAs play important roles in the development of various diseases including inflammatory bowel disease[11,12,13,14]. LncRNAs have been proved to be involved in the regulation of intestinal epithelial cell apoptosis[15, 16], regeneration[17,18,19], and inflammatory response[20, 21]. We previously identified a lncRNA, named Gm31629, which is abundant in bone marrow mesenchymal cells (BMSCs) and hypothalamic neural stem cells (htNSCs) at early ages of mice[14, 22]

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Conclusion