Global Epigenomic Analysis of Primary Human Pancreatic Islets Provides Insights into Type 2 Diabetes Susceptibility Loci

被引：153

作者：

Stitzel, Michael L. ^{[1
]}

Sethupathy, Praveen ^{[1
]}

Pearson, Daniel S. ^{[1
]}

Chines, Peter S. ^{[1
]}

Song, Lingyun ^{[3
]}

Erdos, Michael R. ^{[1
]}

Welch, Ryan ^{[5
]}

Parker, Stephen C. J. ^{[1
]}

Boyle, Alan P. ^{[3
]}

Scott, Laura J. ^{[5
]}

Margulies, Elliott H. ^{[1
]}

Boehnke, Michael ^{[5
]}

Furey, Terrence S. ^{[3
]}

Crawford, Gregory E. ^{[3
,4
]}

Collins, Francis S. ^{[1
]}

机构：

[1] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA

[2] NHGRI, NIH Intramural Sequencing Ctr NISC, NIH, Bethesda, MD 20892 USA

[3] Duke Univ, Inst Genome Sci & Policy, Durham, NC 27708 USA

[4] Duke Univ, Dept Pediat, Div Med Genet, Durham, NC 27708 USA

[5] Univ Michigan, Ctr Stat Genet, Dept Biostat, Ann Arbor, MI 48109 USA

来源：

CELL METABOLISM | 2010年 / 12卷 / 05期

关键词：

RANGE CHROMOSOMAL INTERACTIONS; GENOME-WIDE ASSOCIATION; INSULIN-SECRETION; BETA-CELLS; OPEN CHROMATIN; HISTONE MODIFICATIONS; REGULATORY ELEMENTS; GENE-EXPRESSION; BINDING-SITES; IN-VIVO;

D O I：

10.1016/j.cmet.2010.09.012

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：443 / 455

页数：13

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