Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1.

Department of Pediatrics, Children's Hospital of Philadelphia, Department of Medicine, and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Journal of Clinical Investigation (Impact Factor: 13.77). 07/2008; 118(6):2316-24. DOI: 10.1172/JCI33655
Source: PubMed

ABSTRACT Intrauterine growth retardation (IUGR) has been linked to the onset of diseases in adulthood, including type 2 diabetes, and has been proposed to result from altered gene regulation patterns due to epigenetic modifications of developmental genes. To determine whether epigenetic modifications may play a role in the development of adult diabetes following IUGR, we used a rodent model of IUGR that expresses lower levels of Pdx1, a pancreatic and duodenal homeobox 1 transcription factor critical for beta cell function and development, which develops diabetes in adulthood. We found that expression of Pdx1 was permanently reduced in IUGR beta cells and underwent epigenetic modifications throughout development. The fetal IUGR state was characterized by loss of USF-1 binding at the proximal promoter of Pdx1, recruitment of the histone deacetylase 1 (HDAC1) and the corepressor Sin3A, and deacetylation of histones H3 and H4. Following birth, histone 3 lysine 4 (H3K4) was demethylated and histone 3 lysine 9 (H3K9) was methylated. During the neonatal period, these epigenetic changes and the reduction in Pdx1 expression could be reversed by HDAC inhibition. After the onset of diabetes in adulthood, the CpG island in the proximal promoter was methylated, resulting in permanent silencing of the Pdx1 locus. These results provide insight into the development of type 2 diabetes following IUGR and we believe they are the first to describe the ontogeny of chromatin remodeling in vivo from the fetus to the onset of disease in adulthood.

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    • "The high glucose in turn triggers epigenetic changes in the progeny DNA, often resulting in gestational diabetes in the next generation. Studies in rats with the proximal promoter region of Pdx1, a duodenal and pancreatic specific homeobox transcription factor reveal that onset of diabetes was associated with permanent silencing of the locus (Park et al., 2008). "
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    ABSTRACT: Epigenetics has the potential to explain various biological phenomena that have heretofore defied complete explication. This review describes the various types of endogenous human developmental milestones such as birth, puberty, and menopause, as well as the diverse exogenous environmental factors that influence human health, in a chronological epigenetic context. We describe the entire course of human life from periconception to death and chronologically note all of the potential internal timepoints and external factors that influence the human epigenome. Ultimately, the environment presents these various factors to the individual that influence the epigenome, and the unique epigenetic and genetic profile of each individual also modulates the specific response to these factors. During the course of human life, we are exposed to an environment that abounds with a potent and dynamic milieu capable of triggering chemical changes that activate or silence genes. There is constant interaction between the external and internal environments that is required for normal development and health maintenance as well as for influencing disease load and resistance. For example, exposure to pharmaceutical and toxic chemicals, diet, stress, exercise, and other environmental factors are capable of eliciting positive or negative epigenetic modifications with lasting effects on development, metabolism and health. These can impact the body so profoundly as to permanently alter the epigenetic profile of an individual. We also present a comprehensive new hypothesis of how these diverse environmental factors cause both direct and indirect epigenetic changes and how this knowledge can ultimately be used to improve personalized medicine.
    Frontiers in Cell and Developmental Biology 09/2014; 2(49). DOI:10.3389/fcell.2014.00049
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    • "In addition, it has been suggested that HFD during fetal development induces glucagon (GLU) cell hypertrophy and hyperplasia, resulting in an increase in GLU cell number and volume in the neonatal offspring (Cerf et al. 2005). These findings could be partially explained by altered expression of growth factors, such as insulin-like growth factors (IGFs) and regulatory proteins involved in endocrine cell differentiation, such as the transcription factor pancreatic and duodenal homeobox 1 (PDX1; Park et al. 2008, Chen et al. 2012). Specifically, HFD exposure during development reduced Pdx1 immunoreactivity in a rodent model, indicating that Pdx1 is susceptible to IU environment (Cerf et al. 2009). "
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    ABSTRACT: Malnutrition in utero (IU) could alter pancreatic development. Reported here are the effects of high fat diet (HFD) during pregnancy on fetal growth and pancreatic morphology in an 'At Risk' animal model of metabolic disease, the glucose transporter 4 heterozygous mouse (G4+/-). Wild type (WT) female mice mated with G4+/- males were fed HFD or control (CD) diet for 2 weeks prior to mating and throughout pregnancy. At embryonic day18.5 fetuses were sacrificed and pancreata isolated for analysis of morphology and expression of genes involved in insulin-cell development, proliferation, apoptosis, glucose transport and function. Compared to WT CD, WT HFD fetal pancreata had a 2.4 fold increase in the number of glucagon cells (p=0.023). HFD also increased glucagon cell size by 18% in WT pancreata compared to WT CD. Compared to WT CD, G4+/- CD had an increased number of insulin cells, and decreased insulin and glucagon cell size. Compared to G4+/- CD, G4+/- HFD fetuses had increased pancreatic gene expression of Igf2, a mitogen and inhibitor of apoptosis. Expression of genes involved in proliferation, apoptosis, glucose transport and insulin secretion were not altered in WT HFD compared with G4+/- HFD pancreata. In contrast to WT HFD pancreata, HFD exposure did not alter pancreatic islet morphology in fetuses with GLUT4 haploinsufficiency; this may be mediated in part by increased Igf2 expression. Thus, interactions between IU diet and fetal genetics may play a critical role in the developmental origins of health and disease.
    Journal of Endocrinology 06/2014; DOI:10.1530/JOE-14-0114 · 3.59 Impact Factor
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    • "There is increasing evidence of cross‐talk between DNA methylation and histone modifications (i.e., Hashimshony et al., 2003; Bartke et al., 2010; Hagarman et al., 2013; Spruijt et al., 2013) supporting the idea that these mechanisms act together to regulate gene expression. It is not known how cross‐talk between these two systems is mediated, but data implies that, in at least some circumstances, changes to histone modifications may be induced prior to methylation changes that then serve as more stable epigenetic marks (Park et al., 2008). "
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    ABSTRACT: Epigenetic mechanisms are proposed as an important way in which the genome responds to the environment. Epigenetic marks, including DNA methylation and Histone modifications, can be triggered by environmental effects, and lead to permanent changes in gene expression, affecting the phenotype of an organism. Epigenetic mechanisms have been proposed as key in plasticity, allowing environmental exposure to shape future gene expression. While we are beginning to understand how these mechanisms have roles in human biology and disease, we have little understanding of their roles and impacts on ecology and evolution. In this review, we discuss different types of epigenetic marks, their roles in gene expression and plasticity, methods for assaying epigenetic changes, and point out the future advances we require to understand fully the impact of this field. J. Exp. Zool. (Mol. Dev. Evol.) 9999B: 1–13, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Experimental Zoology Part B Molecular and Developmental Evolution 06/2014; 322(4). DOI:10.1002/jez.b.22571 · 1.88 Impact Factor


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