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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Erdos, Michael R. Chines, Peter S. Black, Brian L. Van Bueren, Kelly Lammerts Narisu, Narisu Orozco, Jose Miguel Taylor, D. Leland Collins, Francis S. Pennacchio, Len A. Akiyama, Jennifer A. Visel, Axel Parker, Stephen C. J. Stitzel, Michael L. |
| Description | Author Affiliation: Parker SC ( National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.); |
| Abstract | Chromatin-based functional genomic analyses and genomewide association studies (GWASs) together implicate enhancers as critical elements influencing gene expression and risk for common diseases. Here, we performed systematic chromatin and transcriptome profiling in human pancreatic islets. Integrated analysis of islet data with those from nine cell types identified specific and significant enrichment of type 2 diabetes and related quantitative trait GWAS variants in islet enhancers. Our integrated chromatin maps reveal that most enhancers are short (median = 0.8 kb). Each cell type also contains a substantial number of more extended (≥ 3 kb) enhancers. Interestingly, these stretch enhancers are often tissue-specific and overlap locus control regions, suggesting that they are important chromatin regulatory beacons. Indeed, we show that (i) tissue specificity of enhancers and nearby gene expression increase with enhancer length; (ii) neighborhoods containing stretch enhancers are enriched for important cell type-specific genes; and (iii) GWAS variants associated with traits relevant to a particular cell type are more enriched in stretch enhancers compared with short enhancers. Reporter constructs containing stretch enhancer sequences exhibited tissue-specific activity in cell culture experiments and in transgenic mice. These results suggest that stretch enhancers are critical chromatin elements for coordinating cell type-specific regulatory programs and that sequence variation in stretch enhancers affects risk of major common human diseases. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 44 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-10-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cell Differentiation Physiology Chromatin Diabetes Mellitus, Type 2 Physiopathology Enhancer Elements, Genetic Genetics Epigenomics Gene Expression Regulation Insulin-Secreting Cells Metabolism Animals Chromatin Immunoprecipitation Gene Expression Profiling Genome-Wide Association Study High-Throughput Nucleotide Sequencing Luciferases Mice Mice, Transgenic Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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