Intrauterine growth restriction (IUGR) increases susceptibility to age-related diseases, including type 2 diabetes (T2DM), and is associated with permanent and progressive changes in gene expression. Our study was designed to test whether epigenomic dysregulation mediates the cellular memory of this intrauterine event. To test this hypothesis, we isolated pancreatic islets from control and IUGR (induced by bilateral uterine artery ligation at day 18 of fetal life) animals at 7 weeks of age. Using the HELP (HpaII tiny fragment enrichment by ligationmediated PCR) assay, we generated the first DNA methylation map at almost 1 million unique sites throughout the rat genome in normal pancreatic islet cells, allowing us to identify the changes that occur as a consequence of IUGR. We validated candidate dysregulated loci with quantitative assays of cytosine methylation and gene expression. IUGR changes cytosine methylation at ϳ1,400 loci (false discovery rate of 4.2%) in male rats at 7 weeks of age, preceding the development of diabetes and thus representing candidate loci for mediating the pathogenesis of metabolic disease that occurs later in life. Epigenetic dysregulation occurred preferentially at conserved intergenic sequences, frequently near genes regulating processes known to be abnormal in IUGR islets, such as vascularization, ␤-cell proliferation, insulin secretion, and cell death, associated with concordant changes in mRNA expression. These results demonstrate that epigenetic dysregulation is a strong candidate for propagating the cellular memory of intrauterine events, causing changes in expression of nearby genes and long term susceptibility to type 2 diabetes.Perturbations in the intrauterine environment resulting in poor fetal growth increase the susceptibility for age-related diseases, particularly type 2 diabetes mellitus (T2DM) 4 and cardiovascular disease (1, 2). Moreover, intrauterine growth restriction (IUGR) can cause permanent and progressive changes in gene expression, affecting important metabolically active tissues such as pancreatic islets (3-6). These changes are often present at birth or during early life, and can precede the development of overt disease in rodents by months and in humans by decades. Although the mechanisms that may mediate the "fetal origin of adult disease" (7) remain unclear, dysregulation of the epigenome could play an important role and may explain the changes in gene expression that are heritably maintained through cell divisions in IUGR animals throughout life (8).We have developed an animal model of IUGR caused by uteroplacental insufficiency, which limits the supply of critical substrates (e.g. nutrients, oxygen, growth factors, and hormones) to the fetus (9). This deficient intrauterine environment affects fetal development through permanent and progressive dysregulation of gene expression and function of susceptible cells (e.g. pancreatic ␤-cells) and leads to the development of T2DM in adulthood (3, 6, 9). In particular, expression of pancreatic and duodenal home...

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