Pro-inflammatory cytokines promote selective transcription of circular RNAs in human pancreatic β cells

Circular RNAs (circRNAs) have recently been implicated in impaired β-cell function in diabetes. Using microarray-based profiling of circRNAs in human EndoC-βH1 cells treated with pro-inflammatory cytokines (interleuklin-1β + interferon-γ), this study aimed at investigating the expression and possible regulatory roles of circRNAs in human β cells. We identified ~5,000 β-cell expressed circRNAs of which 84 were differentially expressed (DE) after cytokine exposure. Pathway analysis of the host genes of the DE circRNAs revealed enrichment for cytokine signaling pathways, indicative of selective transcription of circRNAs from inflammatory genes in response to cytokines. Multiple binding sites for β-cell enriched microRNAs and RNA-binding proteins were observed for the highly upregulated circRNAs, supporting their function as ‘sponges’ or ‘decoys’. We also present evidence for circRNA sequence conservation in multiple species, presence of cytokine-induced regulatory elements and putative protein-coding potential for the DE circRNAs. The study highlights the complex regulatory potential of selectively transcribed circRNAs, which may play a crucial role during immune-mediated β-cell destruction in type 1 diabetes. Human EndoC-βH1 cells were left untreated or exposed to proinflammatory cytokines (IL-1β+IFN-γ) for 24h and 48h (n=3, in each condition). Total RNA from 12 samples (four groups) was extracted and profiled for circRNAs.