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

Abstract

BACKGROUND & AIMSThe mammalian intestinal epithelium is colonized by complex microbiota and exposed to a wide variety of luminal noxious substances. Intestinal epithelial integrity is commonly disrupted in patients with critical disorders, but the exact underlying mechanisms are unclear. Long noncoding RNAs transcribed from ultraconserved regions (T‐UCRs) control different cell functions and are involved in gut pathologies. Here, we investigated the role of T‐UCRs in intestinal epithelial homeostasis and identified T‐UCR uc.230 as a major regulator of epithelial renewal, apoptosis, and barrier function.METHODSIntestinal mucosal tissues were collected from mice following dextran sodium sulfate (DSS) treatment or fasting, and from patients with ulcerative colitis and Crohn’s disease. We isolated primary enterocytes from the small intestine of mice and developed intestinal organoids. 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.RESULTSCompared with controls, intestinal mucosal tissues from mice with DSS‐induced colitis or fasted for 48 h and from patients with ulcerative colitis had increased levels of uc.230. The uc.230 content in Crohn’s disease tissues was the same as in control tissue. 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.CONCLUSIONSOur 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.