# Long noncoding RNA GAS5 disrupts intestinal epithelial barrier function by increasing small vault RNA levels

## TL;DR

The study shows that the long noncoding RNA GAS5 harms gut lining integrity by reducing mucosal growth and disrupting tight junctions through increased vault RNA levels.

## Contribution

This paper identifies GAS5 as a novel regulator of intestinal barrier function through its interaction with vault RNAs.

## Key findings

- GAS5 levels increase in intestinal mucosa during colitis and IBD.
- GAS5 represses tight junction proteins and epithelial barrier function.
- GAS5 enhances vault RNA levels, which contributes to barrier dysfunction.

## Abstract

Disruptions in the integrity of the intestinal epithelium occur commonly in inflammatory bowel disease (IBD) and critical surgical disorders, but the underlying mechanisms remain largely unknown. Here we identified long noncoding RNA GAS5 as a repressor of intestinal mucosal growth and the function of the gut epithelial barrier. The levels of tissue GAS5/Gas5 increased in mouse intestinal mucosa after colitis and septic stress, as well as in human intestinal mucosa from patients with IBD. Transient and tissue-specific knockdown of Gas5 in mice using CRISPR/Cas9 enhanced the renewal of the mucosa of the small intestine, increased the levels of tight junction (TJ) proteins ZO-1, ZO-2, claudin-1, and claudin-2, and improved gut barrier function. Conversely, ectopic overexpression of GAS5 in intestinal organoids and in cultured intestinal epithelium cells decreased the levels of these TJ proteins and caused epithelial barrier dysfunction. Mechanistic studies revealed that GAS5 acted as a transcriptional enhancer of the gene encoding small noncoding vault RNAs (vtRNAs) and that GAS5 repressed TJ expression by increasing the levels of vtRNAs. Together, our results indicate that GAS5 disrupts the integrity of the intestinal epithelium by impairing mucosal growth and epithelial barrier function and that it represses TJ expression, at least in part, via vtRNAs.

Long noncoding RNA GAS5 damages gut epithelial integrity by inhibiting mucosal growth and disrupting epithelial barrier function via interaction with vult RNAs.