2型糖尿病患者胰岛中PDX-1的DNA甲基化增加及表达降低。
Increased DNA methylation and decreased expression of PDX-1 in pancreatic islets from patients with type 2 diabetes.
作者信息
Yang Beatrice T, Dayeh Tasnim A, Volkov Petr A, Kirkpatrick Clare L, Malmgren Siri, Jing Xingjun, Renström Erik, Wollheim Claes B, Nitert Marloes Dekker, Ling Charlotte
机构信息
Department of Clinical Sciences, Unit of Epigenetics and Diabetes, Lund University Diabetes Centre, Scania University Hospital, 205 02 Malmoe, Sweden.
出版信息
Mol Endocrinol. 2012 Jul;26(7):1203-12. doi: 10.1210/me.2012-1004. Epub 2012 May 8.
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.
胰腺十二指肠同源盒1（PDX-1）的突变可导致人类单基因形式的糖尿病（青少年成熟期糖尿病4型），而在小鼠胰腺β细胞中沉默Pdx-1会导致糖尿病。然而，PDX-1的表观遗传改变是否会影响人类2型糖尿病（T2D）尚未确定。在此，我们分析了55名非糖尿病供体和9名T2D患者的人胰岛中PDX-1的mRNA表达和DNA甲基化情况。我们还进一步研究了克隆β细胞中PDX-1的表观遗传调控。与非糖尿病供体相比，T2D患者的胰岛中PDX-1表达降低（P = 0.0002），并且在人胰岛中与胰岛素表达呈正相关（rho = 0.59，P = 0.000001）以及与葡萄糖刺激的胰岛素分泌呈正相关（rho = 0.41，P = 0.005）。与非糖尿病供体相比，T2D患者胰岛中PDX-1远端启动子和增强子区域的10个CpG位点的DNA甲基化显著增加。PDX-1的DNA甲基化与人胰岛中的基因表达呈负相关（rho = -0.64，P = 0.0000029）。此外，人PDX-1启动子和增强子区域的甲基化抑制了克隆β细胞中的报告基因表达（P = 0.04）。我们的数据进一步表明，高血糖会降低基因表达并增加PDX-1的DNA甲基化，因为糖化血红蛋白（HbA1c）与人胰岛中PDX-1的mRNA表达呈负相关（rho = -0.50，P = 0.0004），与DNA甲基化呈正相关（rho = 0.54，P = 0.00024）。此外，在暴露于高葡萄糖的克隆β细胞中，虽然Pdx-1表达降低，但Pdx-1甲基化和Dnmt1表达增加。总体而言，鉴于T2D患者的胰岛和暴露于高血糖的β细胞中PDX-1的DNA甲基化增加且表达降低，PDX-1的表观遗传修饰可能在T2D的发生发展中起作用。PDX-1的表达水平还与人胰岛中的胰岛素分泌相关。
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