Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci.

Journal Article (Journal Article)

Identifying cis-regulatory elements is important to understanding 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 modifications (K4me1, K4me3, K79me2), and CCCTC factor (CTCF) binding in human islets. This identified ∼18,000 putative promoters (several hundred unannotated and islet-active). Surprisingly, active promoter modifications were absent at genes encoding islet-specific hormones, suggesting a distinct regulatory mechanism. Of 34,039 distal (nonpromoter) regulatory elements, 47% are islet unique and 22% are CTCF bound. In the 18 type 2 diabetes (T2D)-associated loci, we identified 118 putative regulatory elements and confirmed enhancer activity for 12 of 33 tested. Among six regulatory elements harboring T2D-associated variants, two exhibit significant allele-specific differences in activity. These findings present a global snapshot of the human islet epigenome and should provide functional context for noncoding variants emerging from genetic studies of T2D and other islet disorders.

Full Text

Duke Authors

Cited Authors

  • Stitzel, ML; Sethupathy, P; Pearson, DS; Chines, PS; Song, L; Erdos, MR; Welch, R; Parker, SCJ; Boyle, AP; Scott, LJ; NISC Comparative Sequencing Program, ; Margulies, EH; Boehnke, M; Furey, TS; Crawford, GE; Collins, FS

Published Date

  • November 3, 2010

Published In

Volume / Issue

  • 12 / 5

Start / End Page

  • 443 - 455

PubMed ID

  • 21035756

Pubmed Central ID

  • PMC3026436

Electronic International Standard Serial Number (EISSN)

  • 1932-7420

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2010.09.012


  • eng

Conference Location

  • United States