The long non-coding RNA H19 is a target of pro-inflammatory cytokines in human beta cells and modulates apoptosis and insulin secretion.

The loss of insulin-producing beta cells during type 1 diabetes is mediated by infiltrating immune cells and pro-inflammatory cytokines. Dysregulation of several long-noncoding RNAs (lncRNAs) has been shown to contribute to the destruction and dysfunction of the beta cells. Here, we explored the transcriptome-wide modulation of lncRNAs in human pancreatic islets in response to pro-inflammatory cytokines and evaluated the functional role of one of the top candidates in human beta-cell models.
In this study, human pancreatic islets, 1.1B4, and EndoC-βH5 cells were exposed to the cytokine IFNγ, with or without IL-1β and/or TNFα. To study the lncRNA transcriptome, we analyzed RNA-Seq data from human pancreatic islets of five donors. Our analysis revealed differential expression of 1,169 lncRNAs. H19, a maternally imprinted intergenic lncRNA, was among the top downregulated lncRNAs. H19 downregulation was validated in RNA-Seq data on EndoC-βH1 and EndoC-βH5 cells and verified by real-time qPCR in EndoC-βH5 and 1.1B4 cells. The role of H19 in beta-cell function and death was explored by locked nucleic acid (LNA) GapmeR-mediated knockdown and H19 overexpression by CRISPR activation (CRISPRa). Preliminary results indicate that silencing of H19 causes elevated levels of cytokine-induced caspase-3/7 activity, indicative of increased apoptosis, whereas overexpression of H19 augments glucose-stimulated insulin secretion. Our findings suggest that the lncRNA H19 exerts anti-apoptotic and insulin secretory-modulating effects in pancreatic beta cells, which could play a role during the development of type 1 diabetes.