title: Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants.
abstract: Type 2 diabetes affects over 300 million people, causing severe complications and premature death, yet the underlying molecular mechanisms are largely unknown. Pancreatic islet dysfunction is central in type 2 diabetes pathogenesis, and understanding islet genome regulation could therefore provide valuable mechanistic insights. We have now mapped and examined the function of human islet cis-regulatory networks. We identify genomic sequences that are targeted by islet transcription factors to drive islet-specific gene activity and show that most such sequences reside in clusters of enhancers that form physical three-dimensional chromatin domains. We find that sequence variants associated with type 2 diabetes and fasting glycemia are enriched in these clustered islet enhancers and identify trait-associated variants that disrupt DNA binding and islet enhancer activity. Our studies illustrate how islet transcription factors interact functionally with the epigenome and provide systematic evidence that the dysregulation of islet enhancers is relevant to the mechanisms underlying type 2 diabetes.
authors.affiliation: Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Pasquali
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Oxford, United Kingdom.|Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Gaulton
authors.affiliation: Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Santiago A
authors.initials: SA
authors.lastname: Rodríguez-Seguí
authors.affiliation: Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.
authors.forename: Loris
authors.initials: L
authors.lastname: Mularoni
authors.affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, United Kingdom.
authors.forename: Irene
authors.initials: I
authors.lastname: Miguel-Escalada
authors.affiliation: Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.
authors.forename: İldem
authors.initials: İ
authors.lastname: Akerman
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD) CSIC-UPO-Junta de Andalucía, Sevilla, Spain.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Tena
authors.affiliation: Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Ignasi
authors.initials: I
authors.lastname: Morán
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD) CSIC-UPO-Junta de Andalucía, Sevilla, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Gómez-Marín
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Oxford, United Kingdom.|Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Martijn
authors.initials: M
authors.lastname: van de Bunt
authors.affiliation: Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Joan
authors.initials: J
authors.lastname: Ponsa-Cobas
authors.affiliation: Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Castro
authors.affiliation: Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Takao
authors.initials: T
authors.lastname: Nammo
authors.affiliation: Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Inês
authors.initials: I
authors.lastname: Cebola
authors.affiliation: Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: García-Hurtado
authors.affiliation: Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Maestro
authors.affiliation: University of Lille 2, INSERM U859 Biotherapies Diabete, Lille, France.
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.affiliation: Clinical Transplant Unit, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
authors.affiliation: Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Switzerland.
authors.forename: Thierry
authors.initials: T
authors.lastname: Berney
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Oxford, United Kingdom.|Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
authors.affiliation: Centre de Recherche de l'Institut du Cerveau et de la Moelle, Biotechnology & Biotherapy team, CNRS UMR7225; INSERM U975; University Pierre et Marie Curie, Paris.
authors.forename: Philippe
authors.initials: P
authors.lastname: Ravassard
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD) CSIC-UPO-Junta de Andalucía, Sevilla, Spain.
authors.forename: José Luis Gómez
authors.initials: JLG
authors.lastname: Skarmeta
authors.affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, United Kingdom.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Müller
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Oxford, United Kingdom.|Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.|Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
mesh_terms: D001483:Base Sequence; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005557:Formaldehyde; D005786:Gene Expression Regulation / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism*; D008969:Molecular Sequence Data; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D064878:Web Browser
chemical_list: D002843:Chromatin; D014157:Transcription Factors; D005557:Formaldehyde