Cytosine Methylation Dysregulation in Neonates Following Intrauterine Growth Restriction

Department of Obstetrics, Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, New York, United States of America.
PLoS ONE (Impact Factor: 3.53). 01/2010; 5(1):e8887. DOI: 10.1371/journal.pone.0008887
Source: PubMed

ABSTRACT Perturbations of the intrauterine environment can affect fetal development during critical periods of plasticity, and can increase susceptibility to a number of age-related diseases (e.g., type 2 diabetes mellitus; T2DM), manifesting as late as decades later. We hypothesized that this biological memory is mediated by permanent alterations of the epigenome in stem cell populations, and focused our studies specifically on DNA methylation in CD34+ hematopoietic stem and progenitor cells from cord blood from neonates with intrauterine growth restriction (IUGR) and control subjects.
Our epigenomic assays utilized a two-stage design involving genome-wide discovery followed by quantitative, single-locus validation. We found that changes in cytosine methylation occur in response to IUGR of moderate degree and involving a restricted number of loci. We also identify specific loci that are targeted for dysregulation of DNA methylation, in particular the hepatocyte nuclear factor 4alpha (HNF4A) gene, a well-known diabetes candidate gene not previously associated with growth restriction in utero, and other loci encoding HNF4A-interacting proteins.
Our results give insights into the potential contribution of epigenomic dysregulation in mediating the long-term consequences of IUGR, and demonstrate the value of this approach to studies of the fetal origin of adult disease.

Download full-text


Available from: Reid F Thompson, Nov 11, 2014
1 Follower
  • Source
    • "Some of the observed DNA methylation changes were shown to persist into early infancy (Cooper et al., 2012; Khulan et al., 2012). Similar to fetal adaption to maternal malnutrition, neonates with intrauterine growth restriction exhibited specific changes in DNA methylation, in particular the hepatocyte factor 4 alpha (HNF4A) gene (Einstein et al., 2010). Consistent with evidence from animal models, these studies in humans suggest that the nutritional environment in which the human embryo and fetus develops can influence the epigenetic programming of gene activity in later life. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The epidemic increase of type 2 diabetes and obesity in developed countries cannot be explained by overnutrition, physical inactivity and/or genetic factors alone. Epidemiologic evidence suggests that an adverse intrauterine environment, in particular a shortage or excess of nutrients is associated with increased risks for many complex diseases later in life. An impressive example for the "fetal origins of adult disease" is gestational diabetes mellitus which usually presents in 1% to greater than 10% of third-trimester pregnancies. Intrauterine hyperglycemia is not only associated with increased perinatal morbidity and mortality, but also with increased lifelong risks of the exposed offspring for obesity, metabolic, cardiovascular, and malignant diseases. Accumulating evidence suggests that fetal overnutrition (and similarly undernutrition) lead to persistent epigenetic changes in developmentally important genes, influencing neuroendocrine functions, energy homeostasis and metabolism. The concept of fetal programming has important implications for reproductive medicine. Because during early development the epigenome is much more vulnerable to environmental cues than later in life, avoiding adverse environmental factors in the periconceptional and intrauterine period may be much more important for the prevention of adult disease than any (i.e. dietetic) measures in infants and adults. A successful pregnancy should not primarily be defined by the outcome at birth but also by the health status in later life.
    Molecular Human Reproduction 03/2013; 19(7). DOI:10.1093/molehr/gat020 · 3.48 Impact Factor
  • Source
    • "Secondly, the epigenetic changes detected in our synthetic polyploids, albeit subtle, may have caused modifications in the expression of relevant genes. The chance that small methylation changes are likely to exert an effect on the phenotype has been described previously (Gemma et al., 2009; Einstein et al., 2010). Therefore, it would be interesting to study the whole-genome expression patterns of our diploid and tetraploid materials as well as other mechanisms regulating gene expression, such as histone modifications and chromatin states. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Polyploidy is very common within angiosperms, and several studies are in progress to ascertain the effects of early polyploidization at the molecular, physiological, and phenotypic level. Extensive studies are available only in synthetic allopolyploids. By contrast, less is known about the consequences of autopolyploidization. The current study aimed to assess the occurrence and extent of genetic, epigenetic, and anatomical changes occurring after oryzaline-induced polyploidization of Solanum commersonii Dunal and Solanum bulbocastanum Dunal, two diploid (2n=2×=24) potato species widely used in breeding programmes. Microsatellite analysis showed no polymorphisms between synthetic tetraploids and diploid progenitors. By contrast, analysis of DNA methylation levels indicated that subtle alterations at CG and CHG sites were present in tetraploids of both species. However, no change occurred concurrently in all tetraploids analysed with respect to their diploid parent, revealing a stochastic trend in the changes observed. The morpho-anatomical consequences of polyploidization were studied in leaf main veins and stomata. With only a few exceptions, analyses showed no clear superiority of tetraploids in terms of leaf thickness and area, vessel number, lumen size and vessel wall thickness, stomata pore length and width, guard cell width, and stomatal density compared with their diploid progenitors. These results are consistent with the hypothesis that there are no traits systematically associated with autopolyploidy.
    Journal of Experimental Botany 01/2013; 64(2):625-35. DOI:10.1093/jxb/ers357 · 5.79 Impact Factor
  • Source
    • "A fundamental question relevant to diabetes and its complications is whether subtle environmental cues such as transient hyperglycemia could confer gene-regulating changes. There is intense general interest in explaining long-lasting gene-regulating changes associated with diabetic complications (Katari et al. 2009; Vaquero and Reinberg 2009; Einstein et al. 2010; Thompson et al. 2010). However, the mechanism by which hyperglycemia regulates differential gene expression patterns and associated epigenomic changes in primary cell types is currently unknown. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Emerging evidence suggests that poor glycemic control mediates post-translational modifications to the H3 histone tail. We are only beginning to understand the dynamic role of some of the diverse epigenetic changes mediated by hyperglycemia at single loci, yet elevated glucose levels are thought to regulate genome-wide changes, and this still remains poorly understood. In this article we describe genome-wide histone H3K9/K14 hyperacetylation and DNA methylation maps conferred by hyperglycemia in primary human vascular cells. Chromatin immunoprecipitation (ChIP) as well as CpG methylation (CpG) assays, followed by massive parallel sequencing (ChIP-seq and CpG-seq) identified unique hyperacetylation and CpG methylation signatures with proximal and distal patterns of regionalization associative with gene expression. Ingenuity knowledge-based pathway and gene ontology analyses indicate that hyperglycemia significantly affects human vascular chromatin with the transcriptional up-regulation of genes involved in metabolic and cardiovascular disease. We have generated the first installment of a reference collection of hyperglycemia-induced chromatin modifications using robust and reproducible platforms that allow parallel sequencing-by-synthesis of immunopurified content. We uncover that hyperglycemia-mediated induction of genes and pathways associated with endothelial dysfunction occur through modulation of acetylated H3K9/K14 inversely correlated with methyl-CpG content.
    Genome Research 09/2011; 21(10):1601-15. DOI:10.1101/gr.116095.110 · 13.85 Impact Factor
Show more