A map of open chromatin in human pancreatic islets

Tissue-specific transcriptional regulation is central to human disease1. To identify regulatory DNA active in human pancreatic islets, we measured nucleosome loss by FAIRE (Formaldehyde-Assisted Isolation of Regulatory Elements)2-4 coupled with high-throughput sequencing. We identified ~80,000 discrete open chromatin regions encompassing 1.0% of genomic sequence. We compared islet FAIRE-seq to five non-islet-cell lines, and discovered ~3,100 broad clusters of islet-selective open chromatin sites, which typically encompassed single genes exhibiting tissue-specific expression. We mapped SNPs to open chromatin sites, and found that rs7903146, a TCF7L2 intronic variant strongly associated with type 2 diabetes (T2D)5 is located in open chromatin. We show that rs7903146 heterozygote islets exhibit allelic imbalance in FAIRE signal, and that the variant alters enhancer activity. This indicates that genetic variation at the TCF7L2 T2D susceptibility locus causes local changes in chromatin state. These data provide novel insights into the tissue-specific organization of cis regulatory elements, and show that FAIRE-seq can guide identification of regulatory variants important for disease.