Park, J. H., Stoffers, D. A., Nicholls, R. D. & Simmons, R. A. Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J. Clin. Invest. 118, 2316-2324

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: 13.22). 07/2008; 118(6):2316-24. DOI: 10.1172/JCI33655
Source: PubMed


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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    • "There is growing evidence that intra-uterine exposure to malnutrition can predispose the offspring to metabolic complications including β-cell dysfunction and diabetes later in life (Ravelli et al., 1998; Roseboom et al., 2006). This theory is commonly referred to as the “thrifty phenotype hypothesis” (Hales, 2001) and is thought to be mediated primarily through environmentally induced epigenetic changes to key metabolic regulators (Park et al., 2008; Bramswig and Kaestner, 2012). However, first and second generation progeny of mice exposed to gestational diabetes were found to have impaired glucose tolerance with hypermethylation of the H19 ICR in islets (Ding et al., 2012). "
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    ABSTRACT: Diabetes mellitus represents a group of complex metabolic diseases that result in impaired glucose homeostasis, which includes destruction of β-cells or the failure of these insulin-secreting cells to compensate for increased metabolic demand. Despite a strong interest in characterizing the transcriptome of the different human islet cell types to understand the molecular basis of diabetes, very little attention has been paid to the role of long non-coding RNAs (lncRNAs) and their contribution to this disease. Here we summarize the growing evidence for the potential role of these lncRNAs in β-cell function and dysregulation in diabetes, with a focus on imprinted genomic loci.
    Frontiers in Genetics 07/2014; 5:200. DOI:10.3389/fgene.2014.00200
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    • "PDX-1 expression is controlled at epigenetic(Park et al., 2008; Ma et al., 2010; Yang et al., 2012), transcriptional (Wu et al., 1997; Gupta et al., 2008; Sun et al., 2008; da Silva Xavier et al., 2010), post-translational [phosphorylation (Lebrun et al., 2005; An et al., 2006, 2010; Boucher et al., 2006; Humphrey et al., 2010), ubiquitination (Lebrun et al., 2005; Boucher et al., 2006; Humphrey et al., 2010; Kim et al., 2011b), and sumoylation (Kishi et al., 2003)] levels. SSTR5 knockdown-induced increase of PDX-1 expression is accompanied by an increased expression of PDX-1 mRNA, while overexpression of SSTR5 inhibits PDX-1 mRNA expression (Zhou et al., 2012), indicating that SSTR5 acts as a negative regulator of PDX-1 at least partially through a mechanism of down-regulating PDX-1 mRNA. "
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    ABSTRACT: Somatostatin (SST) is a regulatory peptide and acts as an endogenous inhibitory regulator of the secretory and proliferative responses of target cells. SST's actions are mediated by a family of seven transmembrane domain G protein-coupled receptors that comprise five distinct subtypes (SSTR1-5). SSTR5 is one of the major SSTRs in the islets of Langerhans. Homeodomain-containing transcription factor pancreatic and duodenal homeobox-1 (PDX-1) is essential for pancreatic development, β cell differentiation, maintenance of normal β cell functions in adults and tumorigenesis. Recent studies show that SSTR5 acts as a negative regulator for PDX-1 expression and that SSTR5 mediates somatostatin's inhibitory effect on cell proliferation and insulin expression/excretion through down-regulating PDX-1 expression. SSTR5 exerts its inhibitory effect on PDX-1 expression at both the transcriptional level by down-regulating PDX-1 mRNA and the post-translational level by enhancing PDX-1 ubiquitination. Identification of PDX-1 as a transcriptional target for SSTR5 may help in guiding the choice of therapeutic cancer treatments.
    Frontiers in Physiology 06/2014; 5:226. DOI:10.3389/fphys.2014.00226 · 3.53 Impact Factor
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