Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci
Open accessAbstract
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.
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Studies of pancreatic islets from nondiabetic donors and patients with T2D have identified epigenetic modifications in genes that potentially affect β-cell function.
“Studies of pancreatic islets from nondiabetic donors ( 19 , 20 ) and patients with T2D ( 21 ) have identified epigenetic modifications in genes that potentially affect β-cell function.”
From β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment (2014) · cites this paper as [20]
The Introduction and Discussion describe epigenomic profiling of human islets and identify chromatin marks at genes important for islet function, including INS. However, Experimental Procedures > Human Islets refers donor clinical information to Table S10; the passages in our copy do not establish that these donors were nondiabetic. The separate citation attached to patients with T2D is not assessed here. (LLM, conf=0.82)
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“Studies of pancreatic islets from nondiabetic donors (19,20) and patients with T2D (21) have identified epigenetic modifications in genes that potentially affect b-cell function.”
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- Authors
- Stitzel, M. L., Sethupathy, P., Pearson, D. S., Chines, P. S., Song, L., Erdos, M. R., Welch, R., Parker, S. C. J., Boyle, A. P., Scott, L. J., Margulies, E. H., Boehnke, M., Furey, T. S., Crawford, G. E., & Collins, F. S.
- Affiliations
- National Institutes of Health (US)
- Duke University (US)
- University of Michigan (US)
- Corresponding author
- Collins, Francis S.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 12
- Issue
- 5
- Pages
- 443-455
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3026436
- OpenAlex
- W2095365870
- Cited by
- 193
- References
- 70
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 4 · 2023: 1 · 2022: 9 · 2021: 10 · 2020: 8 · 2019: 20 · 2018: 11 · 2017: 10 · 2016: 13 · 2015: 14 · 2014: 26 · 2013: 25 · 2012: 22
- FWCI
- 7.94
- Type
- journal article
- Language
- en
- Update notices
- erratum (2010-12-01)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DK062370)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- pancreatic islets, cis-regulatory elements, DNase I hypersensitive sites, histone H3 lysine methylation, CTCF binding, enhancers, non-coding variants
- MeSH terms
- CCCTC-Binding Factor, Deoxyribonuclease I, Diabetes Mellitus, Type 2, HeLa Cells, Histones, Humans, Islets of Langerhans, Lysine, Methylation, Promoter Regions, Genetic, Regulatory Sequences, Nucleic Acid, Repressor Proteins, Genome-Wide Association Study, Genetic Loci, Epigenomics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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