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

Caroline Frørup, Tina Fløyel, Aashiq Hussain Mirza, Cecilie Amalie Søndergaard Svane, Maikel L. Colli, Jesper Johannesen, Décio L. Eizirik, Joachim Størling, Claudia Kutter, Flemming Pociot, Simranjeet Kaur*

*Corresponding author af dette arbejde


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.
StatusUdgivet - 2023
BegivenhedIslet Study Group - University of British Columbia, Vancouver, Canada
Varighed: 19 jun. 202321 jun. 2023


KonferenceIslet Study Group
LokationUniversity of British Columbia