Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants
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. Integrate...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS Jg. 110; H. 44; S. 17921 |
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| Hauptverfasser: | , , , , , , , , , , , , |
| Format: | Journal Article |
| Sprache: | Englisch |
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United States
29.10.2013
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| ISSN: | 1091-6490, 1091-6490 |
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| 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. |
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| AbstractList | 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. 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.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. |
| Author | Collins, Francis S Stitzel, Michael L Akiyama, Jennifer A Parker, Stephen C J Taylor, D Leland Chines, Peter S Narisu, Narisu Orozco, Jose Miguel Erdos, Michael R Pennacchio, Len A Black, Brian L Visel, Axel van Bueren, Kelly Lammerts |
| Author_xml | – sequence: 1 givenname: Stephen C J surname: Parker fullname: Parker, Stephen C J organization: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892 – sequence: 2 givenname: Michael L surname: Stitzel fullname: Stitzel, Michael L – sequence: 3 givenname: D Leland surname: Taylor fullname: Taylor, D Leland – sequence: 4 givenname: Jose Miguel surname: Orozco fullname: Orozco, Jose Miguel – sequence: 5 givenname: Michael R surname: Erdos fullname: Erdos, Michael R – sequence: 6 givenname: Jennifer A surname: Akiyama fullname: Akiyama, Jennifer A – sequence: 7 givenname: Kelly Lammerts surname: van Bueren fullname: van Bueren, Kelly Lammerts – sequence: 8 givenname: Peter S surname: Chines fullname: Chines, Peter S – sequence: 9 givenname: Narisu surname: Narisu fullname: Narisu, Narisu – sequence: 10 givenname: Brian L surname: Black fullname: Black, Brian L – sequence: 11 givenname: Axel surname: Visel fullname: Visel, Axel – sequence: 12 givenname: Len A surname: Pennacchio fullname: Pennacchio, Len A – sequence: 13 givenname: Francis S surname: Collins fullname: Collins, Francis S |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24127591$$D View this record in MEDLINE/PubMed |
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| Snippet | Chromatin-based functional genomic analyses and genomewide association studies (GWASs) together implicate enhancers as critical elements influencing gene... |
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| SubjectTerms | Animals Cell Differentiation - physiology Chromatin - physiology Chromatin Immunoprecipitation Diabetes Mellitus, Type 2 - genetics Diabetes Mellitus, Type 2 - physiopathology Enhancer Elements, Genetic - genetics Enhancer Elements, Genetic - physiology Epigenomics - methods Gene Expression Profiling Gene Expression Regulation - genetics Gene Expression Regulation - physiology Genome-Wide Association Study High-Throughput Nucleotide Sequencing Humans Insulin-Secreting Cells - metabolism Insulin-Secreting Cells - physiology Luciferases Mice Mice, Transgenic |
| Title | Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants |
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