title: Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants.
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.
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Stephen C J
authors.initials: SC
authors.lastname: Parker
authors.forename: Michael L
authors.initials: ML
authors.lastname: Stitzel
authors.forename: D Leland
authors.initials: DL
authors.lastname: Taylor
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Orozco
authors.forename: Michael R
authors.initials: MR
authors.lastname: Erdos
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Akiyama
authors.forename: Kelly Lammerts
authors.initials: KL
authors.lastname: van Bueren
authors.forename: Peter S
authors.initials: PS
authors.lastname: Chines
authors.forename: Narisu
authors.initials: N
authors.lastname: Narisu
authors.forename: Brian L
authors.initials: BL
authors.lastname: Black
authors.forename: Axel
authors.initials: A
authors.lastname: Visel
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002843:Chromatin / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology*; D004742:Enhancer Elements, Genetic / Q000235:genetics* / Q000502:physiology; D057890:Epigenomics / Q000379:methods*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000502:physiology; D008156:Luciferases; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D002843:Chromatin; D008156:Luciferases