The IBD associated long non-coding RNA IFNG-AS1 regulates the balance between inflammatory and anti-inflammatory cytokine production after T-cell stimulation.

The inflammatory bowel diseases (IBD) are a complex set of chronic gastrointestinal inflammatory conditions arising from the interplay of genetic and environmental factors. This study focuses on non-coding RNA transcripts as potential mediators of IBD pathophysiology. One particular gene, interferon gamma-antisense 1 (IFNG-AS1), has been consistently observed to be elevated in the intestinal mucosa of actively inflamed IBD patients versus healthy controls. This study builds on these observations demonstrating that the second splice variant is specifically altered and this alteration even stratifies within inflamed patients. Using a CRISPR-based over-expression system, IFNG-AS1 was selectively overexpressed directly from its genomic loci in T-cells. An unbiased mRNA array on these cells identified a large increase in many inflammatory cytokines and a decrease in anti-inflammatory cytokines after IFNG-AS1 over-expression. Media from T-cells overexpressing IFNG-AS1 elicited an inflammatory signaling cascade in primary human peripheral blood mononuclear cells, suggesting the potential functional importance of IFNG-AS1 in IBD pathophysiology. The significance of these results is amplified by studies suggesting that a single nucleotide polymorphism in IFNG-AS1, rs7134599, was associated with both subtypes of IBD patients independently of race.