Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci.
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.
Duke Scholars
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Related Subject Headings
- Repressor Proteins
- Regulatory Sequences, Nucleic Acid
- Promoter Regions, Genetic
- Methylation
- Lysine
- Islets of Langerhans
- Humans
- Histones
- Hela Cells
- HeLa Cells
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Repressor Proteins
- Regulatory Sequences, Nucleic Acid
- Promoter Regions, Genetic
- Methylation
- Lysine
- Islets of Langerhans
- Humans
- Histones
- Hela Cells
- HeLa Cells