Characterizing the role of GATA6-AS1 long non-coding RNA in epithelial pathogenesis of Crohn Disease

The inflammatory bowel diseases (IBD), Crohn disease (CD) and ulcerative colitis (UC), are caused by pathogenic interactions between the gut microbiota, environmental factors, and genetics, leading to chronic activation of the immune system and epithelial injury. Current treatment options are suboptimal leading to less than 50% sustained healing. Long non-coding RNAs (lncRNA) play fundamental roles in gene expression regulation and are an emerging novel research field.

As part of our translational research, we have analyzed the largest treatment naïve cohort of 304 pediatric CD and controls, and identified 459 dysregulated lncRNA in CD. We showed that many lncRNA have reduced expression specifically in CD epithelia. Prioritizing the CD dysregulated lncRNA by expression and tissue specificity emphasized that many of the down regulated CD lncRNA are induced during Caco-2 cell model differentiation. One such lncRNA is GATA6-AS1 that is expressed mainly in the nucleus.

Reducing GATA6-AS1 levels showed significant reduction of the neighboring gene GATA6 expression, a transcription factor that plays a role in differentiation and protects epithelial cells from bacterial infection. GATA6-AS1 downregulation also reduced LGR5, an epithelial stem cells gene located at the crypt base and a key factor in epithelial renewal. Interestingly, GATA6-AS1 RNA pull-down followed by mass-spectrometry, revealed several proteins related to metabolic and mitochondrial activity. In conclusion, proper epithelial homeostasis and metabolic functions are future potential treatment goal of CD, and boosting GATA6-AS1 lncRNAs function to improve epithelial homeostasis may serve as new target for RNA-based interventions with less off-target affects, due to its tissue specificity.