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

Area of Science:

• Gastroenterology
• Molecular Biology
• Immunology

Background:

• Intestinal epithelial barrier integrity is crucial for gut health, with disruptions common in inflammatory bowel diseases (IBD) and surgical disorders.
• The molecular mechanisms underlying intestinal barrier dysfunction remain largely unknown.

Purpose of the Study:

• To identify novel regulators of intestinal mucosal growth and gut barrier function.
• To investigate the role of long noncoding RNA GAS5 in intestinal epithelial integrity.

Main Methods:

• CRISPR-Cas9 mediated knockdown of GAS5 in mouse models.
• Analysis of tight junction (TJ) protein expression and gut barrier function.
• Overexpression of GAS5 in intestinal organoids and cultured epithelial cells.
• Mechanistic studies involving small noncoding vault RNAs (vtRNAs).

Main Results:

• GAS5 levels were elevated in mouse models of colitis/sepsis and in human IBD mucosa.
• GAS5 knockdown in mice enhanced mucosal renewal, increased TJ proteins (ZO-1, ZO-2, claudin-1, claudin-2), and improved barrier function.
• GAS5 overexpression impaired TJ protein levels and epithelial barrier function.
• GAS5 enhances vtRNA transcription, which in turn represses TJ expression.

Conclusions:

• GAS5 acts as a repressor of intestinal mucosal growth and gut barrier function.
• GAS5 disrupts intestinal integrity partly by increasing vtRNA levels, leading to repression of TJ expression.
• GAS5 represents a potential therapeutic target for conditions involving intestinal barrier dysfunction.