Identifying cis-regulatory elements is important to understand how human pancreatic islets modulate gene expression in physiologic or pathophysiologic (e.g., diabetic) conditions. We conducted genome-wide analysis of DNase I hypersensitive sites, histone H3 lysine methylation marks (K4me1, K4me3, K79me2), and CCCTC factor (CTCF) binding in human islets. This identified ~18,000 putative promoters (several hundred novel and islet-active). Surprisingly, active promoter marks were absent at genes encoding islet-specific hormones, suggesting a distinct regulatory mechanism. Of 34,039 distal (non-promoter) regulatory elements, 47% are islet-unique and 22% are CTCF-bound. These findings present a global snapshot of the human islet epigenome and should provide functional context for non-coding variants emerging from genetic studies of T2D and other pancreatic islet disorders. Three different islet samples were tested for DNase I hypersensitivity by DNase-Seq. Five different primary pancreatic islet samples were evaluated for several chromatin modifications (H3K4me3, H3K4me1, H3K79me2) by ChIP-seq. One islet sample was evaluated for CTCF binding via ChIP-seq, All ChIP-seq samples have both non-specific IP (GFP) and input DNA controls.

Identify cis-regulatory elements important for modulating gene expression in human pancreatic islets.

Genome-wide analyses of DNaseI hypersensitive sites, histone H3 lysine methylation (H3K4me1, H3K4me3, H3K79me2), and CTCF-binding in unstimulated human islets were performed using DNase-Seq and ChIP-Seq on the Illumina GAII platform. Peaks were called using MACS for DNAseI hypersensitive, H3K4me3, and CTCF-binding sites. Comparisons were made to the related study, Gaulton et al. Nature Genetics 2010

DNase-Seq led to identification of 101,326 DNaseI hypersensitive peaks in human islets. Overlap with stringent FAIRE-Seq peaks was ~ 75% (97% at transcription start sites. About 18,000 putative promoters were identified including several hundred unannotated ones active in islets. The islet-specific hormones did not have active promoter modifications suggesting a distinct regulatory mechanism. Of 34,039 non-promoter regulatory elements, 47% are islet unique and 22% are CTCF bound. 118 putative regulatory elements were found in 18 T2D-associated loci for which 12 of 33 had confirmed enhancer activity. Significant allele-specific differences were seen in 2 of 6 regulatory elements harboring T2D-associated variants. Those elements were associated with TCF7L2 and WFS1

A global snapshot of the human islet epigenome was generated providing a context for noncoding variants found in T2D genetic studies.

• islet epigenomics: 3918, 4075, 4078, 4114, 4175, 4235, 4395, 4514,