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Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets.

ABSTRACT: Type 2 diabetes mellitus (T2DM) is a complex disease characterized by the inability of the insulin-producing ? 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 ? 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 ? 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.

SUBMITTER: Kameswaran V

PROVIDER: S-EPMC3932527 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets.

Kameswaran Vasumathi V Bramswig Nuria C NC McKenna Lindsay B LB Penn Melinda M Schug Jonathan J Hand Nicholas J NJ Chen Ying Y Choi Inchan I Vourekas Anastassios A Won Kyoung-Jae KJ Liu Chengyang C Vivek Kumar K Naji Ali A Friedman Joshua R JR Kaestner Klaus H KH

Cell metabolism 20131226 1

Type 2 diabetes mellitus (T2DM) is a complex disease characterized by the inability of the insulin-producing β 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 β cel ...[more]

PMID: 24374217

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Project description:Insulin secretion in pancreatic islets is dependent upon mitochondrial function and production of ATP. The transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator-1 alpha (protein PGC-1alpha; gene PPARGC1A) is a master regulator of mitochondrial genes and its expression is decreased and related to impaired oxidative phosphorylation in muscle from patients with type 2 diabetes. Whether it plays a similar role in human pancreatic islets is not known. We therefore investigated if PPARGC1A expression is altered in islets from patients with type 2 diabetes and whether this expression is influenced by genetic (PPARGC1A Gly482Ser polymorphism) and epigenetic (DNA methylation) factors. We also tested if experimental downregulation of PPARGC1A expression in human islets influenced insulin secretion.The PPARGC1A Gly482Ser polymorphism was genotyped in human pancreatic islets from 48 non-diabetic and 12 type 2 diabetic multi-organ donors and related to PPARGC1A mRNA expression. DNA methylation of the PPARGC1A promoter was analysed in pancreatic islets from ten type 2 diabetic and nine control donors. Isolated human islets were transfected with PPARGC1A silencing RNA (siRNA).PPARGC1A mRNA expression was reduced by 90% (p<0.005) and correlated with the reduction in insulin secretion in islets from patients with type 2 diabetes. After downregulation of PPARGC1A expression in human islets by siRNA, insulin secretion was reduced by 41% (p <or= 0. 01). We were able to ascribe reduced PPARGC1A expression in islets to both genetic and epigenetic factors, i.e. a common PPARGC1A Gly482Ser polymorphism was associated with reduced PPARGC1A mRNA expression (p<0.00005) and reduced insulin secretion (p<0.05). In support of an epigenetic influence, the PPARGC1A gene promoter showed a twofold increase in DNA methylation in diabetic islets compared with non-diabetic islets (p<0.04).We have shown for the first time that PPARGC1A might be important in human islet insulin secretion and that expression of PPARGC1A in human islets can be regulated by both genetic and epigenetic factors.

Dataset Information

Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets.

Publications

Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets.

Similar Datasets

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