Genome-wide DNA Methylation Profiles Associated with Abnormal Intrauterine Growth

Summary

Principal Investigator: Cristina Montagna
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2009-09-10 - 2014-06-30
more information: NIH RePORT

Top Publications

  1. pmc Diabetes in pregnancy: glycemia control guidelines and rationale
    Scarlett D Karakash
    Department of Obstetrics and Gynecology and Women s Health, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Curr Opin Endocrinol Diabetes Obes 18:99-103. 2011
  2. ncbi Perinephric and epididymal fat affect hepatic metabolism in rats
    Shani Ben-Shlomo
    The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Obesity (Silver Spring) 20:151-6. 2012
  3. pmc Minireview: Epigenetics of obesity and diabetes in humans
    Howard Slomko
    Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA
    Endocrinology 153:1025-30. 2012
  4. pmc RAD51 mutants cause replication defects and chromosomal instability
    Tae Moon Kim
    Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center, San Antonio, Texas, USA
    Mol Cell Biol 32:3663-80. 2012
  5. pmc Multigenerational effects of maternal undernutrition
    Francine H Einstein
    Department of Obstetrics and Gynecology and Women s Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA Electronic address
    Cell Metab 19:893-4. 2014

Detail Information

Publications6

  1. pmc Diabetes in pregnancy: glycemia control guidelines and rationale
    Scarlett D Karakash
    Department of Obstetrics and Gynecology and Women s Health, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Curr Opin Endocrinol Diabetes Obes 18:99-103. 2011
    ..Today, after several large multicenter clinical trials, we are closer than ever to a national and international consensus...
  2. ncbi Perinephric and epididymal fat affect hepatic metabolism in rats
    Shani Ben-Shlomo
    The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Obesity (Silver Spring) 20:151-6. 2012
    ..In conclusion, PEVF has a deleterious effect on the liver as a source of insulin resistance-inducing adipokines irrespective of diet, and does not serve as a buffer for excess nutrients...
  3. pmc Minireview: Epigenetics of obesity and diabetes in humans
    Howard Slomko
    Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA
    Endocrinology 153:1025-30. 2012
    ..In this review, we present recent progress in epigenetics of human obesity and diabetes, existing challenges, and the potential for new approaches to unravel the complex biology of metabolic dysregulation...
  4. pmc RAD51 mutants cause replication defects and chromosomal instability
    Tae Moon Kim
    Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center, San Antonio, Texas, USA
    Mol Cell Biol 32:3663-80. 2012
    ..We found very low levels of mutant protein present at these sites compared to normal protein, suggesting that low levels of mutant protein were sufficient for disruption of RAD51 activity and generation of chromosomal rearrangements...
  5. pmc Multigenerational effects of maternal undernutrition
    Francine H Einstein
    Department of Obstetrics and Gynecology and Women s Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA Electronic address
    Cell Metab 19:893-4. 2014
    ..Martínez et al. (2014) demonstrate multigenerational effects of poor maternal nutrition and evidence of germline transmission through alterations in DNA methylation...

Research Grants32

  1. Biosynthesis and Function of Lactosaminyl Glycans in Hematopoiesis
    Robert Sackstein; Fiscal Year: 2013
    ..This research effort should yield new treatments to improve marrow function in such conditions. (End of Abstract) ..
  2. Prenatal stress and epigenetic programming of the HPA axis and autonomic balance
    Rosalind J Wright; Fiscal Year: 2013
    ..This study may begin to inform how this happens at the most basic level. ..
  3. Frontotemporal Dementias: Genotypes and Phenotypes
    Virginia M Lee; Fiscal Year: 2013
    ..elegans and transgenic mouse models. The proposed studies will provide important insights into mechanisms of FTLD and the diagnosis and treatment of these disorders. ..
  4. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
    ..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
  5. Stanford University Center for Reproductive and Stem Cell biology
    Margaret T Fuller; Fiscal Year: 2013
    ..abstract_text> ..
  6. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  7. Egg to Embryo: Gene Regulatory Circuitry in Development
    Eric H Davidson; Fiscal Year: 2013
    ..In the DAVIDSON COMPONENT the GRN will be expanded to include all regulatory genes predicted by genomic analysis, and observed to be expressed specifically in the endomesodermal territories, (cont.) ..
  8. Dissemination of Evidence-Based Health Disparity Interventions
    Ashwini Sehgal; Fiscal Year: 2013
    ..abstract_text> ..
  9. DEVELOPMENT OF NOVEL THERAPIES FOR NIDDM
    Christopher B Newgard; Fiscal Year: 2013
    ..abstract_text> ..
  10. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  11. Epigenetic Effects of Prenatal Arsenic Exposure and Fetal Growth
    Molly L Kile; Fiscal Year: 2013
    ..The proposed studies will fill important research gaps in our knowledge of arsenic toxicity and its impact on fetal growth that could inform both clinical and public health interventions in developing and developed countries. ..
  12. Effects of fetal bisphenol A exposure on mouse epigenome
    Martha Susiarjo; Fiscal Year: 2013
    ..The mouse will be used as a model system in the proposed studies to determine the potential etiology of human diseases with underlying environmental causes. ..
  13. AGE AND TISSUE-SPECIFIC CHANGES IN GENOME-WIDE MAMMALIAN METHYLATION
    Enrique Ramos; Fiscal Year: 2013
    ..abstract_text> ..