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Pancreatic islet enhancer clusters enriched in type 2 diabetes risk–associated variants

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 for type 2 diabetes pathogenesis, and therefore understanding islet genome regulation could provide...

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Autores principales: Pasquali, Lorenzo, Gaulton, Kyle J., Rodríguez-Seguí, Santiago A., Mularoni, Loris, Miguel-Escalada, Irene, Akerman, İldem, Tena, Juan J., Morán, Ignasi, Gómez-Marín, Carlos, van de Bunt, Martijn, Ponsa-Cobas, Joan, Castro, Natalia, Nammo, Takao, Cebola, Inês, García-Hurtado, Javier, Maestro, Miguel Angel, Pattou, François, Piemonti, Lorenzo, Berney, Thierry, Gloyn, Anna L., Ravassard, Philippe, Skarmeta, José Luis Gómez, Müller, Ferenc, McCarthy, Mark I., Ferrer, Jorge
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935450/
https://www.ncbi.nlm.nih.gov/pubmed/24413736
http://dx.doi.org/10.1038/ng.2870
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author Pasquali, Lorenzo
Gaulton, Kyle J.
Rodríguez-Seguí, Santiago A.
Mularoni, Loris
Miguel-Escalada, Irene
Akerman, İldem
Tena, Juan J.
Morán, Ignasi
Gómez-Marín, Carlos
van de Bunt, Martijn
Ponsa-Cobas, Joan
Castro, Natalia
Nammo, Takao
Cebola, Inês
García-Hurtado, Javier
Maestro, Miguel Angel
Pattou, François
Piemonti, Lorenzo
Berney, Thierry
Gloyn, Anna L.
Ravassard, Philippe
Skarmeta, José Luis Gómez
Müller, Ferenc
McCarthy, Mark I.
Ferrer, Jorge
author_facet Pasquali, Lorenzo
Gaulton, Kyle J.
Rodríguez-Seguí, Santiago A.
Mularoni, Loris
Miguel-Escalada, Irene
Akerman, İldem
Tena, Juan J.
Morán, Ignasi
Gómez-Marín, Carlos
van de Bunt, Martijn
Ponsa-Cobas, Joan
Castro, Natalia
Nammo, Takao
Cebola, Inês
García-Hurtado, Javier
Maestro, Miguel Angel
Pattou, François
Piemonti, Lorenzo
Berney, Thierry
Gloyn, Anna L.
Ravassard, Philippe
Skarmeta, José Luis Gómez
Müller, Ferenc
McCarthy, Mark I.
Ferrer, Jorge
author_sort Pasquali, Lorenzo
collection PubMed
description 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 for type 2 diabetes pathogenesis, and therefore understanding islet genome regulation could 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 3D 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 dysregulation of islet enhancers is relevant to the mechanisms underlying type 2 diabetes.
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spelling pubmed-39354502014-08-01 Pancreatic islet enhancer clusters enriched in type 2 diabetes risk–associated variants Pasquali, Lorenzo Gaulton, Kyle J. Rodríguez-Seguí, Santiago A. Mularoni, Loris Miguel-Escalada, Irene Akerman, İldem Tena, Juan J. Morán, Ignasi Gómez-Marín, Carlos van de Bunt, Martijn Ponsa-Cobas, Joan Castro, Natalia Nammo, Takao Cebola, Inês García-Hurtado, Javier Maestro, Miguel Angel Pattou, François Piemonti, Lorenzo Berney, Thierry Gloyn, Anna L. Ravassard, Philippe Skarmeta, José Luis Gómez Müller, Ferenc McCarthy, Mark I. Ferrer, Jorge Nat Genet Article 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 for type 2 diabetes pathogenesis, and therefore understanding islet genome regulation could 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 3D 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 dysregulation of islet enhancers is relevant to the mechanisms underlying type 2 diabetes. 2014-01-12 2014-02 /pmc/articles/PMC3935450/ /pubmed/24413736 http://dx.doi.org/10.1038/ng.2870 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Pasquali, Lorenzo
Gaulton, Kyle J.
Rodríguez-Seguí, Santiago A.
Mularoni, Loris
Miguel-Escalada, Irene
Akerman, İldem
Tena, Juan J.
Morán, Ignasi
Gómez-Marín, Carlos
van de Bunt, Martijn
Ponsa-Cobas, Joan
Castro, Natalia
Nammo, Takao
Cebola, Inês
García-Hurtado, Javier
Maestro, Miguel Angel
Pattou, François
Piemonti, Lorenzo
Berney, Thierry
Gloyn, Anna L.
Ravassard, Philippe
Skarmeta, José Luis Gómez
Müller, Ferenc
McCarthy, Mark I.
Ferrer, Jorge
Pancreatic islet enhancer clusters enriched in type 2 diabetes risk–associated variants
title Pancreatic islet enhancer clusters enriched in type 2 diabetes risk–associated variants
title_full Pancreatic islet enhancer clusters enriched in type 2 diabetes risk–associated variants
title_fullStr Pancreatic islet enhancer clusters enriched in type 2 diabetes risk–associated variants
title_full_unstemmed Pancreatic islet enhancer clusters enriched in type 2 diabetes risk–associated variants
title_short Pancreatic islet enhancer clusters enriched in type 2 diabetes risk–associated variants
title_sort pancreatic islet enhancer clusters enriched in type 2 diabetes risk–associated variants
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935450/
https://www.ncbi.nlm.nih.gov/pubmed/24413736
http://dx.doi.org/10.1038/ng.2870
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