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

Summary, in English

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.

• Författare: Beatrice Yang; Tasnim Dayeh; Petr Volkov; Clare L Kirkpatrick; Siri Malmgren; Xingjun Jing; Erik Renström; Claes Wollheim; Marloes Dekker Nitert; Charlotte Ling
• Avdelning/ar: Translationell Muskel Forskning; Diabetes - epigenetik; Diabetes - molekylär metabolism; Diabetes - öpatofysiologi; EXODIAB: Excellence of Diabetes Research in Sweden
• Publiceringsår: 2012
• Språk: Engelska
• Sidor: 1203-1212
• Publikation/Tidskrift/Serie: Molecular Endocrinology
• Volym: 26
• Issue: 7
• Fulltext: - 697 kB; Download statistics
• Länkar: http://www.ncbi.nlm.nih.gov/pubmed/22570331?dopt=Abstract; http://dx.doi.org/10.1210/me.2012-1004
• Dokumenttyp: Artikel i tidskrift
• Förlag: The Endocrine Society
• Ämne: Endocrinology and Diabetes
• Status: Published
• Forskningsgrupp: Genomics, Diabetes and Endocrinology; Diabetes - Epigenetics; Diabetes - Molecular Metabolism; Diabetes - Islet Patophysiology
• ISBN/ISSN/Övrigt: ISSN: 0888-8809