Human β Cell Transcriptome Analysis Uncovers IncRNAs That Are Tissue-Specific, Dynamically Regulated, and Abnormally Expressed in Type 2 Diabetes

A significant portion of the genome is transcribed as long noncoding RNAs (IncRNAs), several of which are known to control gene expression. The repertoire and regulation of IncRNAs in disease-relevant tissues, however, has not been systematically explored. We report a comprehensive strand-specific transcriptome map of human pancreatic islets and 13 cells, and uncover >1100 intergenic and antisense islet-cell IncRNA genes. We find islet IncRNAs that are dynamically regulated and show that they are an integral component of the beta cell differentiation and maturation program. We sequenced the mouse islet transcriptome and identify IncRNA orthologs that are regulated like their human counterparts. Depletion of HI-LNC25, a beta cell-specific IncRNA, downregulated GLIS3 mRNA, thus exemplifying a gene regulatory function of islet IncRNAs. Finally, selected islet IncRNAs were dysregulated in type 2 diabetes or mapped to genetic loci underlying diabetes susceptibility. These findings reveal a new class of islet-cell genes relevant to beta cell programming and diabetes pathophysiology.