Experimental intrauterine growth restriction induces alterations in DNA methylation and gene expression in pancreatic islets of rats.
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 ligation-mediated 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 approximately 1,400 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, beta-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.
Thompson
Reid F
RF
Departments of Genetics (Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, New York 10461; Center for Epigenomics, Albert Einstein College of Medicine, Bronx, New York, New York 10461.
Fazzari
Melissa J
MJ
Departments of Genetics (Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, New York 10461; Center for Epigenomics, Albert Einstein College of Medicine, Bronx, New York, New York 10461; Departments of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, New York 10461.
Niu
Hongshun
H
Center for Research on Reproduction and Women's Health, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104.
Barzilai
Nir
N
Departments of Medicine, Albert Einstein College of Medicine, Bronx, New York, New York 10461.
Simmons
Rebecca A
RA
Center for Research on Reproduction and Women's Health, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104. Electronic address: rsimmons@mail.med.upenn.edu.
Greally
John M
JM
Departments of Genetics (Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, New York 10461; Center for Epigenomics, Albert Einstein College of Medicine, Bronx, New York, New York 10461; Departments of Medicine, Albert Einstein College of Medicine, Bronx, New York, New York 10461. Electronic address: john.greally@einstein.yu.edu.
D000818:Animals; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D007515:Islets of Langerhans / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley