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

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Autores principales:	Pasquali, L., Gaulton, K.J., Rodríguez-Seguí, S.A., Mularoni, L., Miguel-Escalada, I., Akerman, I., Tena, J.J., Morán, I., Gómez-Marín, C., Van De Bunt, M., Ponsa-Cobas, J., Castro, N., Nammo, T., Cebola, I., García-Hurtado, J., Maestro, M.A., Pattou, F., Piemonti, L., Berney, T., Gloyn, A.L., Ravassard, P., Skarmeta, J.L.G., Müller, F., Mccarthy, M.I., Ferrer, J.
Formato:	JOUR
Materias:	glucose transcription factor article chromatin controlled study DNA binding enhancer region epigenetics gene cluster gene control gene disruption gene sequence genetic association genetic risk genetic variability glucose blood level human non insulin dependent diabetes mellitus nonhuman pancreas insufficiency pancreas islet pathogenesis priority journal Base Sequence Chromatin Chromatin Immunoprecipitation Diabetes Mellitus, Type 2 Electrophoretic Mobility Shift Assay Enhancer Elements, Genetic Formaldehyde Gene Expression Regulation Gene Regulatory Networks Genome-Wide Association Study Humans Islets of Langerhans Molecular Sequence Data Sequence Analysis, RNA Transcription Factors Web Browser
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_10614036_v46_n2_p136_Pasquali
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	todo:paper_10614036_v46_n2_p136_Pasquali
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spelling	todo:paper_10614036_v46_n2_p136_Pasquali2023-10-03T16:01:08Z Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants Pasquali, L. Gaulton, K.J. Rodríguez-Seguí, S.A. Mularoni, L. Miguel-Escalada, I. Akerman, I. Tena, J.J. Morán, I. Gómez-Marín, C. Van De Bunt, M. Ponsa-Cobas, J. Castro, N. Nammo, T. Cebola, I. García-Hurtado, J. Maestro, M.A. Pattou, F. Piemonti, L. Berney, T. Gloyn, A.L. Ravassard, P. Skarmeta, J.L.G. Müller, F. Mccarthy, M.I. Ferrer, J. glucose transcription factor article chromatin controlled study DNA binding enhancer region epigenetics gene cluster gene control gene disruption gene sequence genetic association genetic risk genetic variability glucose blood level human non insulin dependent diabetes mellitus nonhuman pancreas insufficiency pancreas islet pathogenesis priority journal Base Sequence Chromatin Chromatin Immunoprecipitation Diabetes Mellitus, Type 2 Electrophoretic Mobility Shift Assay Enhancer Elements, Genetic Formaldehyde Gene Expression Regulation Gene Regulatory Networks Genome-Wide Association Study Humans Islets of Langerhans Molecular Sequence Data Sequence Analysis, RNA Transcription Factors Web Browser 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. © 2014 Nature America, Inc. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_10614036_v46_n2_p136_Pasquali
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	glucose transcription factor article chromatin controlled study DNA binding enhancer region epigenetics gene cluster gene control gene disruption gene sequence genetic association genetic risk genetic variability glucose blood level human non insulin dependent diabetes mellitus nonhuman pancreas insufficiency pancreas islet pathogenesis priority journal Base Sequence Chromatin Chromatin Immunoprecipitation Diabetes Mellitus, Type 2 Electrophoretic Mobility Shift Assay Enhancer Elements, Genetic Formaldehyde Gene Expression Regulation Gene Regulatory Networks Genome-Wide Association Study Humans Islets of Langerhans Molecular Sequence Data Sequence Analysis, RNA Transcription Factors Web Browser
spellingShingle	glucose transcription factor article chromatin controlled study DNA binding enhancer region epigenetics gene cluster gene control gene disruption gene sequence genetic association genetic risk genetic variability glucose blood level human non insulin dependent diabetes mellitus nonhuman pancreas insufficiency pancreas islet pathogenesis priority journal Base Sequence Chromatin Chromatin Immunoprecipitation Diabetes Mellitus, Type 2 Electrophoretic Mobility Shift Assay Enhancer Elements, Genetic Formaldehyde Gene Expression Regulation Gene Regulatory Networks Genome-Wide Association Study Humans Islets of Langerhans Molecular Sequence Data Sequence Analysis, RNA Transcription Factors Web Browser Pasquali, L. Gaulton, K.J. Rodríguez-Seguí, S.A. Mularoni, L. Miguel-Escalada, I. Akerman, I. Tena, J.J. Morán, I. Gómez-Marín, C. Van De Bunt, M. Ponsa-Cobas, J. Castro, N. Nammo, T. Cebola, I. García-Hurtado, J. Maestro, M.A. Pattou, F. Piemonti, L. Berney, T. Gloyn, A.L. Ravassard, P. Skarmeta, J.L.G. Müller, F. Mccarthy, M.I. Ferrer, J. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants
topic_facet	glucose transcription factor article chromatin controlled study DNA binding enhancer region epigenetics gene cluster gene control gene disruption gene sequence genetic association genetic risk genetic variability glucose blood level human non insulin dependent diabetes mellitus nonhuman pancreas insufficiency pancreas islet pathogenesis priority journal Base Sequence Chromatin Chromatin Immunoprecipitation Diabetes Mellitus, Type 2 Electrophoretic Mobility Shift Assay Enhancer Elements, Genetic Formaldehyde Gene Expression Regulation Gene Regulatory Networks Genome-Wide Association Study Humans Islets of Langerhans Molecular Sequence Data Sequence Analysis, RNA Transcription Factors Web Browser
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 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. © 2014 Nature America, Inc.
format	JOUR
author	Pasquali, L. Gaulton, K.J. Rodríguez-Seguí, S.A. Mularoni, L. Miguel-Escalada, I. Akerman, I. Tena, J.J. Morán, I. Gómez-Marín, C. Van De Bunt, M. Ponsa-Cobas, J. Castro, N. Nammo, T. Cebola, I. García-Hurtado, J. Maestro, M.A. Pattou, F. Piemonti, L. Berney, T. Gloyn, A.L. Ravassard, P. Skarmeta, J.L.G. Müller, F. Mccarthy, M.I. Ferrer, J.
author_facet	Pasquali, L. Gaulton, K.J. Rodríguez-Seguí, S.A. Mularoni, L. Miguel-Escalada, I. Akerman, I. Tena, J.J. Morán, I. Gómez-Marín, C. Van De Bunt, M. Ponsa-Cobas, J. Castro, N. Nammo, T. Cebola, I. García-Hurtado, J. Maestro, M.A. Pattou, F. Piemonti, L. Berney, T. Gloyn, A.L. Ravassard, P. Skarmeta, J.L.G. Müller, F. Mccarthy, M.I. Ferrer, J.
author_sort	Pasquali, L.
title	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_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_sort	pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants
url	http://hdl.handle.net/20.500.12110/paper_10614036_v46_n2_p136_Pasquali
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Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants

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