Human Pancreatic β Cell lncRNAs Control Cell-Specific Regulatory Networks

• DOI: 10.1016/j.cmet.2016.11.016
• Publication Date: 2016-12-29T18:48:01Z
• Authors: Ildem Akerman; Zhidong Tu; Anthony Beucher; Delphine M.Y. Rol...; Claire Sauty-Colace; Marion Benazra; Nikolina Nakic; Jialiang Yang; Huan Wang; Lorenzo Pasquali; Ignasi Moran; Javier Garcia-Hur...; Natalia Castro; Roser Gonzalez-Fr...; Andrew F. Stewart; Caroline Bonner; Lorenzo Piemonti; Thierry Berney; Leif Groop; Julie Kerr-Conte; Francois Pattou; Carmen Argmann; Eric Schadt; Philippe Ravassard; Jorge Ferrer
• Keywords: Transcription, Genetic; Physiology; Messenger; LINCRNAS; MESH: Insulin Secretion; 0601 Biochemistry and Cell Biology; MESH: Insulin-Secreting Cells; TRANSCRIPTIONAL LANDSCAPE; PLUTO; transcriptional networks; Insulin-Secreting Cells; info:eu-repo/classification/ddc/617; Insulin Secretion; Insulin; Gene Regulatory Networks; long noncoding RNAs; CRISPR interference; MESH: Gene Regulatory Networks; GENE-EXPRESSION; PDX1; 0303 health sciences; ddc:617; diabetes; MESH: Transcription Factors; MESH: Gene Expression Regulation; ENDOCRINE PANCREAS; Chromatin; MESH: RNA, Long Noncoding; DIFFERENTIATION; Phenotype; 1101 Medical Biochemistry and Metabolomics; Gene Knockdown Techniques; Multigene Family; Long Noncoding; RNA, Long Noncoding; type 2 diabetes; Transcription; Life Sciences & Biomedicine; Type 2; MESH: Diabetes Mellitus, Type 2; 570; MESH: Trans-Activators; lncRNAs; LINE; MESH: Insulin; MESH: Phenotype; LONG NONCODING RNAS; Article; MESH: Chromatin; Endocrinology & Metabolism; 03 medical and health sciences; Genetic; MESH: Homeodomain Proteins; REVEALS; Diabetes Mellitus; 617; Journal Article; Humans; RNA, Messenger; Molecular Biology; MESH: RNA, Messenger; Homeodomain Proteins; MESH: Humans; Science & Technology; pancreatic islets; MESH: Transcription, Genetic; PDX-1; Cell Biology; MESH: Gene Knockdown Techniques; EVOLUTION; Diabetes Mellitus, Type 2; Gene Expression Regulation; Trans-Activators; RNA; MESH: Multigene Family; chromatin; [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology; Transcription Factors

SummaryRecent studies have uncovered thousands of long non-coding RNAs (IncRNAs) in human pancreatic β cells. β 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 β cell gene regulation and diabetes, the function of β cell lncRNAs remains largely unknown. In this study, we investigated the function of β 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 β cell-specific transcriptional networks. We further demonstrate that lncRNAPLUTOaffects local three-dimensional chromatin structure and transcription ofPDX1,encoding a key β cell transcription factor, and that bothPLUTOandPDX1are downregulated in islets from donors with type 2 diabetes or impaired glucose tolerance. These results implicate lncRNAs in the regulation of β cell-specific transcription factor networks.