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Title

Increased DNA methylation and decreased expression of PDX-1 in pancreatic islets from patients with type 2 diabetes

Authors
Yang, Beatrice T
Dayeh, Tasnim A
Volkov, Petr A
Malmgren, Siri
Jing, Xingjun
Renström, Erik
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Published in Molecular Endocrinology. 2012, vol. 26, no. 7, p. 1203-12
Abstract Mutations in pancreatic duodenal homeobox 1 (PDX-1) can cause a monogenic form of diabetes (maturity onset diabetes of the young 4) in humans, and silencing Pdx-1 in pancreatic β-cells of mice causes diabetes. However, it is not established whether epigenetic alterations of PDX-1 influence type 2 diabetes (T2D) in humans. Here we analyzed mRNA expression and DNA methylation of PDX-1 in human pancreatic islets from 55 nondiabetic donors and nine patients with T2D. We further studied epigenetic regulation of PDX-1 in clonal β-cells. PDX-1 expression was decreased in pancreatic islets from patients with T2D compared with nondiabetic donors (P = 0.0002) and correlated positively with insulin expression (rho = 0.59, P = 0.000001) and glucose-stimulated insulin secretion (rho = 0.41, P = 0.005) in the human islets. Ten CpG sites in the distal PDX-1 promoter and enhancer regions exhibited significantly increased DNA methylation in islets from patients with T2D compared with nondiabetic donors. DNA methylation of PDX-1 correlated negatively with its gene expression in the human islets (rho = -0.64, P = 0.0000029). Moreover, methylation of the human PDX-1 promoter and enhancer regions suppressed reporter gene expression in clonal β-cells (P = 0.04). Our data further indicate that hyperglycemia decreases gene expression and increases DNA methylation of PDX-1 because glycosylated hemoglobin (HbA1c) correlates negatively with mRNA expression (rho = -0.50, P = 0.0004) and positively with DNA methylation (rho = 0.54, P = 0.00024) of PDX-1 in the human islets. Furthermore, while Pdx-1 expression decreased, Pdx-1 methylation and Dnmt1 expression increased in clonal β-cells exposed to high glucose. Overall, epigenetic modifications of PDX-1 may play a role in the development of T2D, given that pancreatic islets from patients with T2D and β-cells exposed to hyperglycemia exhibited increased DNA methylation and decreased expression of PDX-1. The expression levels of PDX-1 were further associated with insulin secretion in the human islets.
Keywords DNA MethylationDiabetes Mellitus, Type 2/genetics/metabolismFemaleGlucose/pharmacologyHomeodomain Proteins/biosynthesis/geneticsHumansHyperglycemia/metabolismInsulin/biosynthesisInsulin-Secreting Cells/metabolismMaleMiddle AgedPancreas/metabolismPromoter Regions, GeneticRNA, Messenger/genetics/metabolismTrans-Activators/biosynthesis/genetics
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PMID: 22570331
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YANG, Beatrice T et al. Increased DNA methylation and decreased expression of PDX-1 in pancreatic islets from patients with type 2 diabetes. In: Molecular Endocrinology, 2012, vol. 26, n° 7, p. 1203-12. doi: 10.1210/me.2012-1004 https://archive-ouverte.unige.ch/unige:33356

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Deposited on : 2014-01-16

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