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Stretch enhancers drive cell-specific gene regulation and harbor human disease risk variants

Friday, November 08, 2013 — Poster Session III

10:00 a.m. – 12:00 p.m.

FAES Academic Center (Upper-Level Terrace)



* FARE Award Winner


  • SCJ Parker
  • ML Sitzel
  • DL Taylor
  • JM Orozco
  • MR Erdos
  • JA Akiyama
  • KL van Beuren
  • PS Chines
  • N Narisu
  • BL Black
  • A Visel
  • LA Pennacchio
  • FS Collins


Chromatin-based functional genomic analyses and genome-wide association studies together implicate enhancers as critical elements influencing gene expression and risk for common diseases. Mammalian enhancers range in size from tens to thousands of base pairs but the functional relevance of large enhancers in vivo and in the context of common human diseases remains unexplored. Here, we performed systematic chromatin and transcriptome profiling in human pancreatic islets. Integrated analysis across ten cell types revealed an abundance of large (>3 kb) tissue-specific enhancers. We show that (i) these “stretch enhancers” are significantly enriched for genetic variants associated with traits relevant to the respective cell type; (ii) known locus control regions overlap stretch enhancers; (iii) tissue specificity of enhancers and levels of nearby gene expression increase with enhancer size; and (iv) stretch enhancer-containing neighborhoods are enriched for important cell type-specific genes. Transgenic assays identified examples of tissue-specific in vivo activity of stretch enhancers, including an islet stretch enhancer >164 kb from the nearest gene that targets reporter expression reproducibly to the pancreatic primordium of mouse embryos. Our results indicate that stretch enhancers are critical chromatin features for cell-specific regulatory programs, and that sequence variation in stretch enhancers affects risk of major common human diseases.

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