title: Human Pancreatic β Cell lncRNAs Control Cell-Specific Regulatory Networks.
abstract: Recent studies have uncovered thousands of long non-coding RNAs (lncRNAs) 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 the lncRNA PLUTO affects local 3D chromatin structure and transcription of PDX1, encoding a key β 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 β cell-specific transcription factor networks.
authors.affiliation: Section of Epigenomics and Disease, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom; Genomic Programming of Beta Cells Laboratory, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona 08036, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid 28029, Spain.
authors.forename: Ildem
authors.initials: I
authors.lastname: Akerman
authors.affiliation: Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Tu
authors.affiliation: Section of Epigenomics and Disease, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Beucher
authors.affiliation: Section of Epigenomics and Disease, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Delphine M Y
authors.initials: DMY
authors.lastname: Rolando
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut du cerveau et de la moelle (ICM) - Hôpital Pitié-Salpêtrière, Boulevard de l'Hôpital, Paris 75013, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Sauty-Colace
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut du cerveau et de la moelle (ICM) - Hôpital Pitié-Salpêtrière, Boulevard de l'Hôpital, Paris 75013, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Benazra
authors.affiliation: Section of Epigenomics and Disease, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Nikolina
authors.initials: N
authors.lastname: Nakic
authors.affiliation: Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Jialiang
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid 28029, Spain; Germans Trias i Pujol University Hospital and Research Institute and Josep Carreras Leukaemia Research Institute, Badalona 08916, Spain.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Pasquali
authors.affiliation: Section of Epigenomics and Disease, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Ignasi
authors.initials: I
authors.lastname: Moran
authors.affiliation: Genomic Programming of Beta Cells Laboratory, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona 08036, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid 28029, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Garcia-Hurtado
authors.affiliation: Genomic Programming of Beta Cells Laboratory, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona 08036, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid 28029, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Castro
authors.affiliation: Section of Epigenomics and Disease, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Roser
authors.initials: R
authors.lastname: Gonzalez-Franco
authors.affiliation: Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Stewart
authors.affiliation: European Genomic Institute for Diabetes, INSERM UMR 1190, Lille 59800, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bonner
authors.affiliation: Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milano 20132, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
authors.affiliation: Cell Isolation and Transplantation Center, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Thierry
authors.initials: T
authors.lastname: Berney
authors.affiliation: Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Lund 20502, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.affiliation: European Genomic Institute for Diabetes, INSERM UMR 1190, Lille 59800, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Kerr-Conte
authors.affiliation: European Genomic Institute for Diabetes, INSERM UMR 1190, Lille 59800, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Pattou
authors.affiliation: Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Argmann
authors.affiliation: Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Schadt
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut du cerveau et de la moelle (ICM) - Hôpital Pitié-Salpêtrière, Boulevard de l'Hôpital, Paris 75013, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Ravassard
authors.affiliation: Section of Epigenomics and Disease, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom; Genomic Programming of Beta Cells Laboratory, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona 08036, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid 28029, Spain. Electronic address: jferrerm@imperial.ac.uk.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
mesh_terms: D002843:Chromatin / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D005810:Multigene Family; D010641:Phenotype; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D018398:Homeodomain Proteins; D007328:Insulin; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein
keywords: CRISPR interference; PDX1; PLUTO; chromatin; diabetes; lncRNAs; long noncoding RNAs; pancreatic islets; transcriptional networks; type 2 diabetes