Human Pancreatic β Cell lncRNAs Control Cell-Specific Regulatory Networks

Recent studies have uncovered thousands of long non-coding RNAs (lncRNAs) in human pancreatic beta cells. beta cell lncRNAs are often cell type specific and exhibit dynamic regulation during differentiation or upon changing glucose concentrations. Although these features hint at a role of lncRNAs in beta cell gene regulation and diabetes, the function of beta cell lncRNAs remains largely unknown. In this study, we investigated the function of beta cell-specific lncRNAs and transcription factors using transcript knockdowns and co-expression network analysis. This revealed lncRNAs that function in concert with transcription factors to regulate b cell-specific transcriptional networks. We further demonstrate that the lncRNA PLUTO affects local 3D chromatin structure and transcription of PDX1, encoding a key b cell transcription factor, and that both PLUTO and PDX1 are downregulated in islets from donors with type 2 diabetes or impaired glucose tolerance. These results implicate lncRNAs in the regulation of beta cell-specific transcription factor networks.