Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci - Study GBCO4078
Genomics Study Specifications
|Study Name||Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci|
|Contact Name||Francis S. Collins (NHGRI)|
|My Strategies||Return to My Strategies page|
|Classification||Tissue expression, surveys and comparisons|
|BCBC Release Date||January 04, 2011|
|Public Release Date||January 04, 2011|
|Citation||Stitzel ML, Sethupathy P, Pearson DS, Chines PS, Song L, Erdos MR, Welch R, Parker SC, Boyle AP, Scott LJ, NISC Comparative Sequencing Program, Margulies EH, Boehnke M, Furey TS, Crawford GE, Collins FS. Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci. Cell Metab. 2010. 12:443-55|
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.
|Platform types||TF Binding ChIP-Seq, TF Binding, Open chromatin DNase-Seq, Histone modification ChIP-Seq, Epigenomic|
|Study Design Type||
|Study Factors||Show study factors|
|Study Assays||Show study assays|
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Last modified on Jan 17, 2012
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