As childhood obesity prevalence escalates in developed countries, etiologic studies of obesity have focused on the interaction between genetic variants and modifiable risk factors that encompass energy balance, estimated as caloric intake less caloric expenditure. A compelling alternative explanation is that environmentally induced deregulation of epigenetic mechanisms that guide expression of genes involved in energy balance may culminate in gene expression profiles that predispose to an obese phenotype. Because imprinted genes are regulated by epigenetic mechanisms, and because they are normally expressed from only one parental chromosome, they are particularly susceptible to genetic and/or epigenetic deregulation. Indeed, aberrant DNA methylation at imprint regulatory elements of the paternally expressed growth factor, IGF2, have been associ- ated with increased risk of obesity and overgrowth disorders. DLK1 is elevated in the circulation of obese hu- mans, and both DLK1 and NNAT are involved in adipogenesis. An obesity model in mice was generated through disruption of imprinted Gnasxl. Mechanisms associated with imprint deregulation are only now being unraveled. Feeding female mice a methyl group donor-rich diet during pregnancy triggers altered methylation of the Agouti locus in pups, which subsequently modulates risk of obesity and diabetes. There is a higher pro- pensity for persistent childhood obesity in children born to mothers who smoke during pregnancy, and our data support that IGF2 is epigenetically altered and upregulated in neonates born to smoking mothers. Our central hypothesis is that early exposures increase the risk of epigenetic deregulation of imprinted gene regulatory elements, resulting in altered expression of growth regulatory genes and subsequent rapid weight gain in the offspring, fueling the childhood obesity epidemic.
Our aims are to: (1) Determine if altered methylation of im- printed gene regulatory regions controlling 12 imprinted genes at birth is associated with increased risk of rapid weight gain and obesity in children at age 1, 3 and at 5 years;(2) Determine if in utero exposures to a maternal methyl group donor-rich diet and/or cigarette smoke is associated with increased risk of aberrant DNA methyla- tion at imprinted gene regulatory regions and risk of obesity in children at these ages;(3) Determine if the child's diet (ages 3 and 5 years) is associated with alterations in methylation profiles at these imprint regulatory elements. Genome-wide methylation profiles for ~14,500 genes will also be generated at ages 1 and 5 years to assess the role of methylation in rapid growth and obesity. We will follow 690 participants in our Newborn Epigenetics STudy (NEST) and assess diet, collect anthropometric measurements and buccal cells. We will combine NEST periconceptional, prenatal, parturition and age one year data with data proposed for collection at ages 3 and 5 years to evaluate these exposures in relation to epigenetic changes at imprint regu- latory elements and obesity. Understanding the role of epigenetics in the genesis of childhood obesity will ulti- mately lead to new ways of preventing obesity and associated human diseases.
Public Health Statement of Relevance This longitudinal epidemiology project will study how prenatal and early childhood nutrition affect the function of genes believed to play role in the development of obesity and obesity-related chronic disease. Because nutrition-related patterns of gene deregulation are potentially reversible, identifying nutritional and other risk factors associated with abnormal gene functioning may lead to therapeutic and public health interventions for childhood obesity and for adult onset, obesity-related chronic diseases.
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|Liu, Ying; Hoyo, Cathrine; Murphy, Susan et al. (2013) DNA methylation at imprint regulatory regions in preterm birth and infection. Am J Obstet Gynecol 208:395.e1-7|
|Nye, Monica D; Hoyo, Cathrine; Huang, Zhiqing et al. (2013) Associations between methylation of paternally expressed gene 3 (PEG3), cervical intraepithelial neoplasia and invasive cervical cancer. PLoS One 8:e56325|
|Huang, Zhiqing; Bassil, Christopher F; Murphy, Susan K (2013) Bisulfite sequencing of cloned alleles. Methods Mol Biol 1049:83-94|
|Soubry, Adelheid; Schildkraut, Joellen M; Murtha, Amy et al. (2013) Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort. BMC Med 11:29|
|Huang, Zhiqing; Bassil, Christopher F; Murphy, Susan K (2013) Methylation-specific PCR. Methods Mol Biol 1049:75-82|
|Murphy, Susan K (2013) Prenatal sensitization of a postnatal trigger for metabolic disease. J Clin Invest 123:2786-8|
|Bassil, Christopher F; Huang, Zhiqing; Murphy, Susan K (2013) Bisulfite pyrosequencing. Methods Mol Biol 1049:95-107|
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