Figure 2. Both proximal and distant FAIRE sites harbor functional regulatory elements.

(a) Genes with high expression in islets (top 20%; red) have more FAIRE enrichment at promoters than genes with moderate (middle 20%; green) or low (bottom 20%; blue) expression. (b) Promoters (−750/+250 bp) bound by RNA Pol II, HNF4A or HNF1A in human islets¹¹ are significantly over-represented among islet FAIRE sites (red dash indicates expected value; all bars: P<0.001). (c) Intergenic islet-selective and ubiquitous FAIRE sites that are located >2 kb from a TSS are enriched for evolutionary conserved sequences (P<0.001), predicted regulatory modules (PreMod, P<0.001), and transcription factor binding sites (conserved TFBS and MotifMap, both P<0.001). CTCF binding, however, is enriched in ubiquitous FAIRE sites only. Over half of intergenic open chromatin sites are coincident with an experimentally or computationally determined functional annotation (expected value for random sites: 27%). (d) Open chromatin is most enriched directly at sites of experimentally determined CTCF binding. (e) In contrast to ubiquitous FAIRE sites, islet-selective FAIRE sites are rarely located within 2 kb upstream of a TSS or in exon 1, and are instead located predominantly in more distal regions. Shown is the percentage of bases covered by each annotation category in islet-selective FAIRE sites (blue), ubiquitous FAIRE sites (red), and the mappable genome (gray).