Experimental Intrauterine Growth Restriction Induces Alterations in DNA Methylation and Gene Expression in Pancreatic Islets of Rats

• DOI: 10.1074/jbc.m109.095133
• Publication Date: 2010-03-02T03:55:22Z
• Authors: Reid F. Thompson; Melissa J. Fazzari; Hongshun Niu; Nir Barzilai; Rebecca A. Simmons; John M. Greally
• Keywords: Intrauterine growth restriction; Candidate gene; Pancreatic Islets; Epigenomics

Intrauterine growth restriction (IUGR) increases susceptibility to age-related diseases, including type 2 diabetes (T2DM), and is associated with permanent progressive changes in gene expression. Our study was designed test whether epigenomic dysregulation mediates the cellular memory of this intrauterine event. To hypothesis, we isolated pancreatic islets from control IUGR (induced by bilateral uterine artery ligation at day 18 fetal life) animals 7 weeks age. Using HELP (HpaII tiny fragment enrichment ligation-mediated PCR) assay, generated first DNA methylation map almost 1 million unique sites throughout rat genome normal islet cells, allowing us identify that occur as a consequence IUGR. We validated candidate dysregulated loci quantitative assays cytosine ∼1,400 (false discovery rate 4.2%) male rats age, preceding development thus representing for mediating pathogenesis metabolic disease occurs later life. Epigenetic occurred preferentially conserved intergenic sequences, frequently near genes regulating processes known be abnormal islets, such vascularization, β-cell proliferation, insulin secretion, cell death, concordant mRNA These results demonstrate epigenetic strong propagating events, causing expression nearby long term diabetes.