Type 2 diabetes mellitus (T2DM) is an example of a major age-related disease that has risen dramatically in adults in the last two decades(1). Indeed, the alarming rate of increase in young people is likely to maintain this steep trajectory. Perturbations of the intrauterine environment, marked by the extremes of fetal growth (intrauterine growth restriction (IUGR) and large for gestational age (LGA)), can have major effects in determining long-term disease susceptibility, particularly in regards to T2DM and cardiovascular disease(2). Although the mechanism for this remains imprecise, permanent alterations in gene expression implicate epigenetic regulation, which may serve as the biological memory of fetal conditions and may, in turn, be propagated to subsequent generations creating a transgenerational amplification. The induced adult phenotypic traits associated with IUGR and LGA vary among individuals, but share altered activity of metabolic pathways, homeostatic control processes and tissue structure and function. The commonality of susceptibility to chronic disease and involvement of multiple organ systems is analogous to the normal decline of resistance to disease that occurs with aging and suggests the advancement of this process. The induction of epigenetic alterations in utero may presage the 'age'of an individual, and therefore, susceptibility to age-related diseases, with T2DM being a specific example. We offer a novel hypothesis that conditions during fetal development alter epigenetic patterns of DNA methylation in non-embryonic stem cells, which may be a marker for, or contribute to, susceptibility to T2DM and other age-related diseases. The comparison of DNA methylation profiles induced by exposure to two diametrically opposed intrauterine 'stresses'(IUGR and LGA) may lead to greater insight into the fundamental impact of early life events that create an adult phenotype, which is more susceptible to adult-onset diseases. In addition to being potentially elucidative of the changes that occur in other tissues, the induced epigenetic modifications in this accessible, vitally important population of mulitpotent progenitors may encumber the decline in resistance to disease, thus deferring the increase in susceptibility of chronic disease associated with normal aging. Our first specific aim is to use a high-resolution genome-wide DNA methylation profiling assay, developed at our institution, to comprehensively characterize and make available the global epigenetic patterns of cytosine methylation in a single population of human hematopoietic (CD34+) stem cells isolated from umbilical cord blood of neonates with IUGR, LGA and appropriately grown controls. Our second specific aim is to use the analytic pipelines designed by our group for primary analysis and prioritization of loci, to identify in an unbiased fashion, a set of highly significant and biologically relevant loci for evaluation of functional significance and comparison in other cell types (lymphocytes and leukocytes from umbilical cord and maternal peripheral blood and umbilical vein endothelial cells). The Einstein Center for Epigenomics is a resource for high-throughput molecular technology and the computational epigenomic informatics necessary to analyze massive datasets. The Center, led by one of the PIs (Dr. Greally), is a concentration of individuals with diverse expertise that is committed to leading the advancement of discoveries for epigenomic research and its application to human disease. Understanding the epigenetic underpinning of the developmental contributions to disease susceptibility may aid in the discovery of early life markers that identify individuals at risk for age-related diseases, such as T2DM and result in more effective preventative strategies directed at a specific vulnerable population. Public Health Relevance: Infants born at the extremes of birth weight (i.e. the smallest and largest) are more likely to development type 2 diabetes and other age-related diseases as adults(1). Understanding the contribution of intrauterine conditions to chronic adult disease may lead to the discovery of markers that can be used to identify individuals at risk and may help to prevent chronic disease and premature death.

Public Health Relevance

Infants born at the extremes of birth weight (i.e. the smallest and largest) are more likely to development type 2 diabetes and other age-related diseases as adults(1). Understanding the contribution of intrauterine conditions to chronic adult disease may lead to the discovery of markers that can be used to identify individuals at risk and may help to prevent chronic disease and premature death.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD063791-04
Application #
8301705
Study Section
Special Emphasis Panel (ZRG1-GGG-M (53))
Program Officer
Ilekis, John V
Project Start
2009-09-10
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$394,416
Indirect Cost
$156,816
Name
Albert Einstein College of Medicine
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Delahaye, Fabien; Wijetunga, N Ari; Heo, Hye J et al. (2014) Sexual dimorphism in epigenomic responses of stem cells to extreme fetal growth. Nat Commun 5:5187
Einstein, Francine H (2014) Multigenerational effects of maternal undernutrition. Cell Metab 19:893-4
Wijetunga, N Ari; Delahaye, Fabien; Zhao, Yong M et al. (2014) The meta-epigenomic structure of purified human stem cell populations is defined at cis-regulatory sequences. Nat Commun 5:5195
Slomko, Howard; Heo, Hye J; Einstein, Francine H (2012) Minireview: Epigenetics of obesity and diabetes in humans. Endocrinology 153:1025-30
Ben-Shlomo, Shani; Einstein, Francine H; Zvibel, Isabel et al. (2012) Perinephric and epididymal fat affect hepatic metabolism in rats. Obesity (Silver Spring) 20:151-6
Einstein, Francine H (2012) Challenges of linking early-life conditions and disease susceptibility. Diabetes 61:981-2
Karakash, Scarlett D; Einstein, Francine H (2011) Diabetes in pregnancy: glycemia control guidelines and rationale. Curr Opin Endocrinol Diabetes Obes 18:99-103