Human β cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes.
Morán I., Akerman I., van de Bunt M., Xie R., Benazra M., Nammo T., Arnes L., Nakić N., García-Hurtado J., Rodríguez-Seguí S., Pasquali L., Sauty-Colace C., Beucher A., Scharfmann R., van Arensbergen J., Johnson PR., Berry A., Lee C., Harkins T., Gmyr V., Pattou F., Kerr-Conte J., Piemonti L., Berney T., Hanley N., Gloyn AL., Sussel L., Langman L., Brayman KL., Sander M., McCarthy MI., Ravassard P., Ferrer J.
A significant portion of the genome is transcribed as long noncoding RNAs (lncRNAs), several of which are known to control gene expression. The repertoire and regulation of lncRNAs in disease-relevant tissues, however, has not been systematically explored. We report a comprehensive strand-specific transcriptome map of human pancreatic islets and β cells, and uncover >1100 intergenic and antisense islet-cell lncRNA genes. We find islet lncRNAs that are dynamically regulated and show that they are an integral component of the β cell differentiation and maturation program. We sequenced the mouse islet transcriptome and identify lncRNA orthologs that are regulated like their human counterparts. Depletion of HI-LNC25, a β cell-specific lncRNA, downregulated GLIS3 mRNA, thus exemplifying a gene regulatory function of islet lncRNAs. Finally, selected islet lncRNAs 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 β cell programming and diabetes pathophysiology.