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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.
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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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    • "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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