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

Cell Metab. 2010 Nov 3;12(5):443-55. doi: 10.1016/j.cmet.2010.09.012.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • CCCTC-Binding Factor
  • Deoxyribonuclease I / metabolism*
  • Diabetes Mellitus, Type 2 / genetics*
  • Epigenomics
  • Genetic Loci
  • Genome-Wide Association Study*
  • HeLa Cells
  • Histones / genetics*
  • Histones / metabolism
  • Humans
  • Islets of Langerhans / metabolism*
  • Lysine / metabolism
  • Methylation
  • Promoter Regions, Genetic
  • Regulatory Sequences, Nucleic Acid
  • Repressor Proteins / genetics*


  • CCCTC-Binding Factor
  • CTCF protein, human
  • Histones
  • Repressor Proteins
  • Deoxyribonuclease I
  • Lysine

Associated data

  • GEO/GSE23784