The long noncoding RNA uc.230/CUG-binding protein 1 axis sustains intestinal epithelial homeostasis and response to tissue injury

Abstract

Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control different cell functions and are involved in gut mucosal pathologies. Here, we investigated the role of TUCRs in intestinal epithelium and identified T-UCR uc.230 as a major regulator of epithelial homeostasis. METHODS: Intestinal mucosal tissues were collected from mice treated with 3% DSS in drinking water and from patients with ulcerative colitis and Crohn’s disease. Levels of uc.230 were silenced in intestinal epithelial cells (IECs) and organoids by transfection with small interfering RNAs or elevated using a plasmid vector that overexpressed uc.230. Association of uc.230 with miR-503 was determined by biotinylated RNA pulldown assays. RESULTS: Compared with controls, intestinal mucosal tissues from mice with DSS-induced colitis and from patients with ulcerative colitis had increased levels of uc.230. Silencing uc.230 inhibited the growth of IECs and intestinal organoids and resulted in epithelial barrier dysfunction. Silencing uc.230 also increased IEC vulnerability to apoptotic cell death, whereas increasing uc.230 levels protected IECs against apoptosis. Mechanistic studies revealed that uc.230 increased CUG-binding protein 1 (CUGBP1) by acting as a natural decoy RNA for miR-503, which interacts with Cugbp1 mRNA and represses its translation. CONCLUSIONS: Our results indicate that uc.230 sustains intestinal mucosal homeostasis by promoting epithelial renewal and barrier function and protects IECs against apoptosis at least in part by serving as a natural sponge for miR-503, thereby preserving CUGBP1 expression.