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Cell Metab. 2017 Feb 7;25(2):400-411. doi: 10.1016/j.cmet.2016.11.016. Epub 2016 Dec 29.

Human Pancreatic β Cell lncRNAs Control Cell-Specific Regulatory Networks.

Author information

1
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.
2
Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3
Section of Epigenomics and Disease, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
4
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.
5
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.
6
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.
7
Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
8
European Genomic Institute for Diabetes, INSERM UMR 1190, Lille 59800, France.
9
Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milano 20132, Italy.
10
Cell Isolation and Transplantation Center, University of Geneva, 1211 Geneva 4, Switzerland.
11
Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Lund 20502, Sweden.
12
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.

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.

KEYWORDS:

CRISPR interference; PDX1; PLUTO; chromatin; diabetes; lncRNAs; long noncoding RNAs; pancreatic islets; transcriptional networks; type 2 diabetes

PMID:
28041957
PMCID:
PMC5300904
DOI:
10.1016/j.cmet.2016.11.016
[Indexed for MEDLINE]
Free PMC Article

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