Article

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.

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    • "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. "
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    • "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. "
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