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
Hauptverfasser: Parker, Stephen C J, Stitzel, Michael L, Taylor, D Leland, Orozco, Jose Miguel, Erdos, Michael R, Akiyama, Jennifer A, van Bueren, Kelly Lammerts, Chines, Peter S, Narisu, Narisu, Black, Brian L, Visel, Axel, Pennacchio, Len A, Collins, Francis S
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 29.10.2013
Schlagworte:
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
ISSN:1091-6490, 1091-6490
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.1317023110