Epigenetic Regulation of the DLK1-MEG3 MicroRNA Cluster in Human Type 2 Diabetic Islets

被引：271

作者：

Kameswaran, Vasumathi ^{[1
,3
]}

Bramswig, Nuria C. ^{[1
,3
]}

McKenna, Lindsay B. ^{[1
,3
]}

Penn, Melinda ^{[1
,3
]}

Schug, Jonathan ^{[1
,3
]}

Hand, Nicholas J. ^{[6
]}

Chen, Ying ^{[4
]}

Choi, Inchan ^{[1
,3
]}

Vourekas, Anastassios ^{[5
]}

Won, Kyoung-Jae ^{[1
,3
]}

Liu, Chengyang ^{[2
]}

Vivek, Kumar ^{[2
]}

Naji, Ali ^{[2
,3
]}

Friedman, Joshua R. ^{[6
]}

Kaestner, Klaus H. ^{[1
,3
]}

机构：

[1] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA

[2] Univ Penn, Perelman Sch Med, Dept Surg, Philadelphia, PA 19104 USA

[3] Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA

[4] Univ Penn, Perelman Sch Med, Genom & Computat Biol Grad Program, Philadelphia, PA 19104 USA

[5] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Div Neuropathol, Philadelphia, PA 19104 USA

[6] Childrens Hosp Philadelphia, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Philadelphia, PA 19104 USA

来源：

CELL METABOLISM | 2014年 / 19卷 / 01期

关键词：

EXPRESSION; TARGETS; DOMAIN; IDENTIFICATION; SEQUENCES; REVEALS; GENES; CELLS; GTL2;

D O I：

10.1016/j.cmet.2013.11.016

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Type 2 diabetes mellitus (T2DM) is a complex disease characterized by the inability of the insulin-producing beta cells in the endocrine pancreas to overcome insulin resistance in peripheral tissues. To determine if microRNAs are involved in the pathogenesis of human T2DM, we sequenced the small RNAs of human islets from diabetic and nondiabetic organ donors. We identified a cluster of microRNAs in an imprinted locus on human chromosome 14q32 that is highly and specifically expressed in human beta cells and dramatically downregulated in islets from T2DM organ donors. The downregulation of this locus strongly correlates with hypermethylation of its promoter. Using HITS-CLIP for the essential RISC-component Argonaute, we identified disease-relevant targets of the chromosome 14q32 microRNAs, such as IAPP and TP53INP1, that cause increased beta cell apoptosis upon overexpression in human islets. Our results support a role for microRNAs and their epigenetic control by DNA methylation in the pathogenesis of T2DM.

引用

页码：135 / 145

页数：11

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