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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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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. |
format | Online Article Text |
id | pubmed-3935450 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
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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