Increased DNA Methylation and Decreased Expression of PDX-1 in Pancreatic Islets from Patients with Type 2 Diabetes

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.

Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men

“…It has even been suggested that changes in methylation could actually represent a consequence-and not a cause-of altered transcriptional activity [27]. In addition, the bead array screens a minor portion of the CpG sites in the genome, and we cannot exclude that other regions, such as enhancer regions, are regulatory important for gene expression [28]. All together, the extent to which the observed changes in DNA methylation in this study affect gene expression over time, in a subset of individuals at risk or during certain specific metabolic challenges remain to be determined.…”

Epigenetic dysregulation in pancreatic islets and pathogenesis of type 2 diabetes

“…Two of the most significant DMRs including 164 and 105 CpG sites were located in PDX1 gene, strongly supporting the previous finding of increased methylation and decreased expression of PDX1 in diabetic islets (Figure 1). Glucose increases Pdx1 methylation in mouse clonal β‐cells,7 and a hyperglycemia‐associated single‐nucleotide polymorphism in PDX1 alters PDX1 methylation status in human islets 8. These findings together show that epigenetic modifications of PDX1 could contribute to the development and pathogenesis of type 2 diabetes.…”

“…Differentially methylated regions ( DMR s; red bars) and histone modifications (blue bars) are shown around the PDX 1 region on human chromosome 13. PDX 1 expression levels in control participants (Contl), participants with impaired glucose tolerance ( IGT ) and participants with type 2 diabetes (T2D) are shown on the upper left panel 7. Average methylation levels of DMR s of control and type 2 diabetes participants are shown on the upper right panel 3.…”

Of rodents and men: Species-specific glucose regulation and type 2 diabetes research

“…Human population studies will likely prove invaluable for identifying T2DM susceptibility genes, for drug testing, and for characterization of other aspects of t2DM such as environmental and lifestyle factors. evaluation of epigenetic interactions in glucose regulation can also be studied in T2DM patients (Yang et al, 2012;Volkmar et al, 2012). drugs such as troglitazone, pioglitazone, and rosiglitazone have caused liver disease, myocardial infarctions, and heart failure (Scheen, 2001;Smith, 2003;Taylor and Hobbs, 2009;Nissen and Wolski, 2010).…”