Mammalian genomes are complex, housing a multitude of noncoding RNAs that play vital roles in gene regulation. Among these non-coding RNAs, are vault RNAs (vtRNAs) which are implicated in processes such as mRNA splicing, drug resistance, and tumorigenesis. However, their significance within the intestinal epithelium remains poorly understood. The intestinal epithelium is a critical line of defence against pathogens and harmful substances and relies on tight junctions (TJs) and adherens junctions (AJs) to maintain its integrity. Dysfunctions in this barrier can allow toxic substances and bacteria to enter the bloodstream, increasing the risk of infections and sepsis.
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Professor Jian-Ying Wang and his team of researchers from the Cell Biology Group from the University of Maryland School of Medicine are particularly interested in vtRNA2-1. This gene’s expression is influenced by promoter methylation and is linked to a range of pathologies. Recently, Prof. Wang and his fellow researchers demonstrated that vtRNA expression in the intestinal mucosa changes significantly under stress conditions, particularly in patients with inflammatory bowel disease (IBD). In their investigation, Prof. Wang and his colleagues used a custom lentiviral vector from AMSBIO to boost vtRNA2-1 expression in mice. Their findings have revealed vtRNA2-1 as a potential therapeutic target to protect intestinal epithelium function, particularly in the context of patients suffering IBD.
- vtRNA expression in the intestinal epithelium increases in response to stress. This was observed in mouse models subjected to conditions mimicking colitis and septic stress, as well as in intestinal mucosal tissue from patients with active IBDs ulcerative colitis and Crohn’s disease. These findings indicate the potential involvement of vtRNAs in IBD.
- In vitro studies found vtRNA2-1 contributes to intestinal epithelial barrier dysfunction by reducing the expression of TJ proteins claudin 1, occludin, and AJ protein E-cadherin, which are essential for maintaining the epithelial barrier. Increases in vtRNA2-1 levels were therefore found to impact the epithelial barrier’s function, exacerbating its permeability.
- Ex vivo intestinal organoid models also showed that vtRNA2-1 overexpression disrupts the expression of claudin 1, occludin, and E-cadherin. Elevated vtRNA2-1 levels were also found to impair the function of secretory Paneth cells in the organoids. These effects have implications for the integrity and functioning of the intestinal epithelium.
- Prof. Wang’s team used a custom lentiviral vector from AMSBIO to induce vtRNA2-1 overexpression in mice to produce an in vivo model. Increasing vtRNA2-1 levels in mice exacerbated gut barrier vulnerability to septic stress, leading to increased permeability. Interestingly, vtRNA2-1 overexpression inhibited the growth of the small intestinal mucosa, particularly the proliferating crypt cell population, while having a minimal effect on Paneth cell function.
- An investigation into the mechanism of vtRNA2-1 revealed that it affects the expression of claudin 1, occludin, and E-cadherin post-transcriptionally. Wang and his fellow researchers found that vtRNA2-1 decreases the stability of E-cadherin mRNA, and inhibits the translation of claudin 1 and occludin without affecting their mRNA stability (Figure 1).
- Further exploration showed vtRNA2-1 represses the translation of claudin 1 and occludin by disrupting the RNA-binding protein HuR’s association with their mRNAs. This interaction between vtRNA2-1 and HuR plays a role in regulating epithelial barrier function by preventing HuR from binding to target mRNAs, thus inhibiting their expression (Figure 1).
Prof. Wang’s research at the University of Maryland School of Medicine has revealed vtRNA2-1’s as a key player in gut barrier dysfunction during critical illnesses, through its effects on intestinal stability by influencing specific proteins and interacting with HuR. The elevated vtRNA levels in IBD patients suggests that it is a promising therapeutic target for safeguarding the gut barrier. Wang and his team’s research is paving the way for further exploration of vtRNAs as potential therapeutic targets in various clinical contexts.
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Ma, X. X., Xiao, L., Wen, S. J., Yu, T. X., Sharma, S., Chung, H. K., Warner, B., Mallard, C. G., Rao, J. N., Gorospe, M., & Wang, J. Y. (2023). Small noncoding vault RNA2-1 disrupts gut epithelial barrier function via interaction with HuR. EMBO reports, 24(2), e54925. https://doi.org/10.15252/embr.202254925
Available online at: https://www.embopress.org/doi/full/10.15252/embr.202254925?saml_referrer