Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants
| Autor: | Ferenc Müller, Lorenzo Piemonti, Mark I. McCarthy, Santiago A. Rodríguez-Seguí, Irene Miguel-Escalada, Ildem Akerman, François Pattou, Jorge Ferrer, Miguel Angel Maestro, Joan Ponsa-Cobas, Lorenzo Pasquali, Carlos Gómez-Marín, Martijn van de Bunt, Natalia Castro, Takao Nammo, Ignasi Moran, Anna L. Gloyn, Loris Mularoni, Javier García-Hurtado, José Luis Gómez Skarmeta, Philippe Ravassard, Juan J. Tena, Inês Cebola, Thierry Berney, Kyle J. Gaulton |
|---|---|
| Přispěvatelé: | Pasquali, Lorenzo, Gaulton, Kyle J., RodrÃguez SeguÃ, Santiago A., Mularoni, Lori, Miguel Escalada, Irene, Akerman, Ildem, Tena, Juan J., Morã¡n, Ignasi, Gómez MarÃn, Carlo, Van De Bunt, Martijn, Ponsa Cobas, Joan, Castro, Natalia, Nammo, Takao, Cebola, Inãª, GarcÃa Hurtado, Javier, Maestro, Miguel Angel, Pattou, Franã§oi, Piemonti, Lorenzo, Berney, Thierry, Gloyn, Anna L., Ravassard, Philippe, Skarmeta, José Luis Gómez, Mã¼ller, Ferenc, Mccarthy, Mark I., Ferrer, Jorge, National Research Foundation Singapore, Agency for Science, Technology and Research A*STAR (Singapore), Centro Esther Koplowitz, European Foundation for the Study of Diabetes, Fundación Lilly, National University of Singapore, Junta de Andalucía, Wellcome Trust, Juvenile Diabetes Research Foundation International, European Commission, Ministerio de Economía y Competitividad (España), Pathology/molecular and cellular medicine, Imperial College Healthcare NHS Trust- BRC Funding |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
LIVER
endocrine system diseases Transcription Factor Diabetes Mellitus Type 2/genetics/metabolism Electrophoretic Mobility Shift Assay Type 2 diabetes Web Browser Transcription Factors/genetics/metabolism electrophoretic mobility shift assay Medical and Health Sciences GLUCOSE TYPE 2 DIABETES HUMAN GENOME Gene Regulatory Networks EPIGENOMIC GENETICS & HEREDITY 11 Medical and Health Sciences GENE-EXPRESSION Epigenomics Genetics Gene Regulatory Network geography.geographical_feature_category ddc:617 REGULATORY REGIONS Research Support Non-U.S. Gov't Biological Sciences Islet Chromatin immunoprecipitation Chromatin 3. Good health GENOME Medicina Básica Enhancer Elements Genetic islets of Langerhans Islets of Langerhans/metabolism Life Sciences & Biomedicine Sequence Analysis Type 2 Human EXPRESSION endocrine system Chromatin Immunoprecipitation CIENCIAS MÉDICAS Y DE LA SALUD Enhancer Elements Molecular Sequence Data PROVIDES INSIGHTS Inmunología BETA CELL Biology Gene Expression Regulation/genetics ENHANCER Islets of Langerhans Genetic Formaldehyde Journal Article medicine Diabetes Mellitus Humans FORMALDEHYDE Enhancer Transcription factor Gene Chromatin/genetics/metabolism geography Science & Technology Base Sequence Sequence Analysis RNA Enhancer Elements Genetic/genetics Islets of Langerhan Epigenome 06 Biological Sciences medicine.disease SUPER-ENHANCERS GENE BETA-CELL Diabetes Mellitus Type 2 Gene Expression Regulation chromatin RNA HISTONE MODIFICATIONS Transcription Factors Developmental Biology Gene Regulatory Networks/genetics Genome-Wide Association Study |
| Zdroj: | Nature Genetics, Vol. 46, No 2 (2014) pp. 136-43 Nature genetics, vol 46, iss 2 Digital.CSIC. Repositorio Institucional del CSIC instname Nature Genetics; Vol 46 |
| ISSN: | 1061-4036 |
| Popis: | PMCID: PMC3935450.-- et al. 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. We thank the DIAGRAM and MAGIC consortia, the Singapore Prospective Study Program, the Singapore Consortium of Cohort Studies, the Singapore Indian Eye Study, the Singapore Malay Eye Study and Y.Y. Teo, E.S. Tai, T.Y. Wong, W.Y. Lim and X. Wang (National University of Singapore; funded by the National Medical Research Council of Singapore, Singapore Translational Researcher Award schemes, the Biomedical Research Council of Singapore and the National Research Foundation (NRF) Fellowship scheme). This work was carried out in part at the Centre Esther Koplowitz. This work was funded by grants from a European Foundation for the Study of Diabetes Lilly fellowship (L. Pasquali), the Ministerio de Economía y Competitividad (SAF2011-27086 to J.F., BFU2010-14839 and CSD2007-00008 to J.L.G.S.), the Innovative Medicines Initiative (DIRECT to M.I.M. and J.F.), the Andalusian Government (CVI-3488 to J.L.G.S.), the Biology of Liver and Pancreatic Development and Disease Marie Curie Initial Training Network (F.M. and J.F.), the Wellcome Trust (090532, 98381 and 090367 to M.I.M., 095101 to A.L.G., 101033 to J.F.), Juvenile Diabetes Research Foundation (31-2012-783 to T.B., F.P. and L. Piemonti) and Framework Programme 7 (HEALTH-F4-2007-201413 to M.I.M.). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|